JP2012529461A - Antiviral heterocyclic compounds - Google Patents

Abstract

A compound having the formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein, is hepatitis C Viral NS5b polymerase inhibitor. Also disclosed are compositions and methods for treating HCV infection and for inhibiting HCV replication.

Description

  The present invention provides non-nucleoside compounds of formula I and certain derivatives thereof that are inhibitors of RNA-dependent RNA viral polymerases. These compounds are useful for the treatment of RNA-dependent RNA viral infections. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and in the treatment of hepatitis C infection.

  Hepatitis C virus is the leading cause of chronic liver disease worldwide (Boyer, N. et al., J. Hepatol. 2000 32: 98-112). Patients with HCV infection are at risk of developing cirrhosis and subsequent hepatocellular carcinoma in the liver, and therefore HCV is a major indication for liver transplantation.

  HCV has been classified as a member of the Flaviviridae family of viruses, including the flaviviruses, pestiviruses, and hepaciviruses including hepatitis C virus (Rice, CM, Flaviviridae: The viruses and their replication. In: Fields Virology) , Editors: BN Fields, DM Knipe and PM Howley, Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an enveloped virus that contains a positive-sense single-stranded RNA genome of approximately 9.4 kb. The viral genome is composed of a highly conserved 5 'untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3' UTR.

  HCV genetic analysis identified six major genotypes that differed by more than 30% of the DNA sequence. More than 30 subtypes are classified. In the US, approximately 70% of infected individuals have type 1a and 1b infections. Type 1b is the most common subtype in Asia (X. Forns and J. Bukh, Clinics in Liver Disease 1999 3: 693-716; J. Bukh et al., Semin. Liv. Dis. 1995 15: 41-63). Unfortunately, type 1 infections are more resistant to treatment than type 2 or type 3 genotypes (N. N. Zein, Clin. Microbiol. Rev., 2000 13: 223-235).

  The viral structural proteins contain the nucleocapsid core protein (C) and two envelope glycoproteins E1 and E2. HCV also encodes two proteases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine protease encoded by the NS3 region. These proteases are required to cleave specific regions of the precursor polyprotein into mature peptides. NS5B, the carboxy half of nonstructural protein 5, contains an RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins, NS4A and NS4B, and NS5A (amino terminal half of nonstructural protein 5) is still unknown. Many of the nonstructural proteins encoded by the HCV RNA genome are thought to be involved in RNA replication.

  Currently, limited approved therapies are available for the treatment of HCV infection. New and existing therapeutic approaches for treating HCV infection and inhibiting NS5B polymerase activity of HCV are outlined below: RG Gish, Sem. Liver. Dis., 1999 19: 5; Di Besceglie, AM and Bacon, BR, Scientific American, October: 1999 80-85; G. Lake-Bakaar, Current and Future Therapy for Chronic Hepatitis C Virus Liver Disease, Curr. Drug Targ. Infect Dis. 2003 3 (3): 247-253; P. Hoffmann et al., Recent patent on experimental therapy for hepatitis C virus infection (1999-2002), Exp. Opin. Ther. Patents 2003 13 (11): 1707-1723; MP Walker et al., Promising Candidates for the treatment of chronic hepatitis C, Exp. Opin.Investing. Drugs 2003 12 (8): 1269-1280; S.-L.Tan et al., Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 2002 1: 867-881; JZ Wu and Z. Hong, Targeting NS5B RNA-Dependent RNA Polymerase for Anti-HCV Chemotherapy, Curr. Drug Targ.- Infect. Dis. 2003 3 (3): 207 -219.

  Ribavirin (1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl) -1H- [1,2,4] triazole-3-carboxylic acid Amide; Virazole®) is a synthesized non-interferon-induced broad-spectrum antiviral nucleoside analog. Ribavirin exhibits in vitro activity against several types of DNA and RNA viruses such as Flaviviridae (Gary L. Davis. Gastroenterology 2000 118: S104-S114). In monotherapy, ribavirin reduces serum aminotransferase levels to normal values in 40% of patients, but does not reduce serum levels of HCV-RNA. Ribavirin is also known to exhibit significant toxicity and induce anemia. Viramidine is a ribavirin prodrug that is converted to ribavirin by adenosine deaminase in hepatocytes (J. Z. Wu, Antivir. Chem. Chemother. 2006 17 (1): 33-9).

  Interferon (IFN) has been used for the treatment of chronic hepatitis for the last approximately 10 years. IFN is a glycoprotein produced by immune cells in response to viral infection. Two different types of interferon are recognized: type 1 includes several types of interferon α and one type of interferon β, and type 2 includes interferon γ. Type 1 interferon is mainly produced by infected cells and protects adjacent cells from new infections. IFN inhibits viral replication of many viruses, including HCV, and when used alone to treat hepatitis C infection, IFN suppresses serum HCV-RNA to undetectable levels. In addition, IFN normalizes serum aminotransferase levels. Unfortunately, the effects of IFN are temporary. Treatment cessation results in a 70% recurrence rate, with only 10-15% showing sustained viral response, normal serum alanine transferase levels (Davis, Luke-Bakaar, supra).

  One limitation of early IFN treatment was the rapid removal of protein from the blood. Chemical derivatization of IFN with polyethylene glycol (PEG) yields a protein with significantly improved pharmacokinetic properties. PEGASYS® is a conjugate of interferon α-2a and 40 kD branched monomethoxy PEG, and PEG-INTRON® is a conjugate of interferon α-2b and 12 kD monomethoxy PEG (BA Luxon et al., Clin. Therap. 2002 24 (9): 13631383; A. Kozlowski and JM Harris, J. Control. Release 2001 72: 217-224).

  HCV combination therapy using ribavirin and interferon-α is the current optimal treatment for HCV. The combination of ribavirin and PEG-IFN (below) results in persistent virus (SVR) in 54-56% of patients with type 1 HCV. In the case of type 2 and type 3 HCV, the SVR reaches 80% (Walker, supra). Unfortunately, combination therapy also produces side effects that cause clinical problems. Depressive state, flu-like symptoms and skin reaction are associated with subcutaneous IFN-α, and hemolytic anemia is associated with sustained treatment with ribavirin.

  Currently, a number of potential molecular targets have been identified for the development of drugs used as anti-HCV therapeutics, including NS2-NS3 autoprotease, NS3 protease, NS3 helicase and NS5B polymerase. Inclusive. RNA-dependent RNA polymerase is essential for the replication of single-stranded plus-sense RNA genomes. This enzyme is of great interest among medicinal chemists.

  Nucleoside inhibitors can act as chain terminators or competitive inhibitors that prevent the binding of nucleotides and polymerase. In order to function as a chain terminator, a nucleoside analog must be taken up by cells in vivo and must be converted in vivo to its triphosphate form and compete as a substrate at the polymerase nucleotide binding site. is there. This conversion to the triphosphate is usually mediated by cellular kinases, conferring additional structural restrictions on any nucleoside. Furthermore, this requirement for phosphorylation limits the direct evaluation of nucleosides as cell-based assays as inhibitors of HCV replication (JA Martin et al., US Patent No. 6,846,810; C. Pierra et al. , J. Med. Chem. 2006 49 (22): 6614-6620; JW Tomassini et al., Antimicrob. Agents and Chemother. 2005 49 (5): 2050; JL Clark et al., J. Med. Chem. 2005 48 (17): 2005).

  The compounds of the present invention and isomers thereof and pharmaceutically acceptable salts thereof are also used in combination with each other, and without limitation, interferon, pegylated interferon, ribavirin, protease inhibitor, polymerase inhibitor, Others including the group consisting of molecular interference RNA compounds, antisense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory drugs, antibiotics, antiviral agents and anti-infective compounds When used in combination with other biologically active agents, it is useful for the treatment and prevention of viral infections in living hosts, particularly hepatitis C infections and diseases. Such combination therapies can also be used to treat the compounds of the present invention with other pharmaceutical agents or enhancers such as ribavirin and related compounds, amantadine and related compounds such as interferon-α, interferon-β, interferon-γ And various other forms of interferon, such as pegylated interferon, can be provided simultaneously or sequentially. Furthermore, the combination of ribavirin and interferon can be administered as an additional combination therapy with at least one compound of the invention.

  Other interferons currently under development include Albuinterferon-α-2b (Albuferon), IFN-ω with DUROS, Locteron ™ and Interferon-α-2b XL. As these and other interferons are marketed, they are expected to be used in combination therapy with the compounds of the present invention.

  HCV polymerase inhibitors are other targets for drug discovery, and compounds under development include R-1626, R-7128, IDX184 / IDX102, PF-868554 (Pfizer), VCH-759 (ViroChem), GS -9190 (Gilead), A-837093 and A-848837 (Abbot), MK-3281 (Merck), GSK949614 and GSK625433 (Glaxo), ANA598 (Anadys), VBY708 (ViroBay).

  Inhibitors of HCV NS3 protease have also been identified as potentially useful in the treatment of HCV. Protease inhibitors in clinical trials include VX-950 (Telaprevir, Vertex), SCH 503034 (Broceprevir, Schering), TMC435350 (Tibotec / Medivir) and ITMN-191 (Intermune). Other protease inhibitors in the early stages of development include MK7009 (Merck), BMS-790052 (Bristol Myers Squibb), VBY-376 (Virobay), IDXSCA / IDXSCB (Idenix), BI12202 (Boehringer), VX-500 (Vertex) PHX1766 (Phenomix).

  Other targets under investigation for anti-HCV therapy include cyclophilin inhibitors that inhibit the binding of RNA to NS5b, nitazoxanide, Celgosivir (Migenix), inhibitors of α-glucosidase-1, caspase inhibitors, Toll Like receptor agonists and immunostimulants such as Zadaxin (SciClone).

SUMMARY OF THE INVENTION Currently, there is no prophylactic treatment of hepatitis C virus (HCV), and currently approved therapies that exist only for HCV are limited. New drug design and development is required.

［式中、
Ｘ^１は、Ｎであり、そして、Ｘ^２、Ｘ^３及びＸ^４は、ＣＲ^５であるか；あるいは、
Ｘ^１及びＸ^２は、Ｎであり、そして、Ｘ^３及びＸ^４は、ＣＲ^５であるか；あるいは、
Ｘ^１、Ｘ^２及びＸ^４は、ＣＲ^５であり、そして、Ｘ^３が、Ｎであるか；あるいは、
Ｘ^１及びＸ^４は、Ｎであり、そして、Ｘ^２及びＸ^３は、ＣＲ^５であるか；あるいは、
Ｘ^１、Ｘ^２、Ｘ^３及びＸ^４は、ＣＲ^５であり；
Ｒ^１は、（ａ）ピリジニル、２−オキソ−１，２−ジヒドロ−ピリジン−３−イル、３−オキソ−３，４−ジヒドロ−ピラジン−２−イル、３−オキソ−２，３−ジヒドロ−ピリダジン−４−イル、２−オキソ−１，２−ジヒドロ−ピリミジン−４−オン−５−イル、６−オキソ−１，６−ジヒドロ−［１，２，４］トリアジン−５−イル、２，４−ジオキソ−３，４−ジヒドロ−２Ｈ−ピリミジン−１−イル、２−オキソ−２（Ｈ）−ピリジン−１−イル、６−オキソ−６Ｈ−ピリダジン−１−イル、６−オキソ−６Ｈ−ピリミジン−１−イル及び２−オキソ−２Ｈ−ピラジン−１−イルからなる群より選択されるヘテロアリール基であり、前記ヘテロアリールは、ハロゲン、Ｃ_１−６アルキル、Ｃ_１−３ハロアルキル、Ｃ_１−６ヒドロキシアルキル、Ｃ_１−３アルコキシ−Ｃ_１−３アルキル、Ｃ_１−６アルコキシ、Ｘ^１（ＣＨ_２）_１−６ＣＯ_２Ｈ又はＸ^１−（ＣＨ_２）_２−６ＮＲ^ｇＲ^ｈにより場合により置換されているか、あるいは；
（ｂ）２−オキソ−テトラヒドロ−ピリミジン−１−イル、２−オキソ−イミダゾリジン−１−イル、２−オキソ−ピペリジン−１−イル、２−オキソ−ピロリジン−１−イル、２，６−ジオキソ−テトラヒドロ−ピリミジン−１−イル、２，４−ジオキソ−１，２，３，４−テトラヒドロ−ピリミジン−５−イル及び２，５−ジオキソ−イミダゾリジン−１−イル及び２，４−ジオキソ−テトラヒドロ−ピリミジン−１−イルからなる群より選択される複素環基であり；
Ｒ^２は、水素、Ｃ_１−６アルコキシ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６ハロアルコキシ又はハロゲンであり；
Ｒ^３は、（ａ）アリール、
（ｂ）ヘテロアリール（ここで、前記アリール又は前記ヘテロアリールは、ヒドロキシ、Ｃ_１−６アルコキシ、Ｃ_１−６アルキル、Ｃ_１−６ヒドロキシアルキル、ハロゲン、（ＣＨ_２）_ｎＮＲ^ｃＲ^ｄ、シアノ、Ｃ_１−６アルコキシカルボニル、カルバモイル、Ｎ−アルキルカルバモイル、Ｎ，Ｎ−ジアルキルカルバモイル、（ＣＨ_２）_０−３ＣＯ_２Ｈ、ＳＯ_２ＮＨ_２、Ｃ_１−６アルキルスルフィニル及びＣ_１−６アルキルスルホニルからなる群より選択される１〜３個の置換基で場合により独立して置換されている）、
（ｃ）ＮＲ^ａＲ^ｂ、
（ｄ）水素、
（ｅ）ハロゲン、
又は、（ｆ）−Ｘ（Ｒ^７）［Ｃ（Ｒ^６）］_２−６ＮＲ^ｅＲ^ｆ（式中、Ｘは、Ｏ若しくはＮＲ^７であり、そして、
Ｒ^７は、水素又はＣ_２−４アルキルであり、
Ｒ^６は、出現ごとに独立して、水素、Ｃ_１−３アルキルであるか、あるいは、
同じ炭素上の２個のＲ^６残基は、Ｃ_２−５アルキレンであるか、あるいは、
異なる炭素上の２個のＲ^６残基は、Ｃ_１−４アルキレンである）であり；
Ｒ^ａ及びＲ^ｂは、それらが結合する窒素と一緒になって、Ｃ_１−６アルキル、ハロゲン又は（ＣＨ_２）_ｎＮＲ^ｅＲ^ｆから独立して選択される１〜３個の基により独立して置換されている環状アミンであり；
Ｒ^ｃ及びＲ^ｄは、独立して、水素、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６アシル、ＳＯ_２Ｒ^８であり、Ｒ^８は、（ａ）Ｃ_１−６アルキル、（ｂ）Ｃ_１−６ハロアルキル、（ｃ）Ｃ_３−７シクロアルキル、（ｄ）Ｃ_３−７シクロアルキル−Ｃ_１−３アルキル、（ｅ）Ｃ_１−６アルコキシ−Ｃ_１−６アルキル又は（ｆ）ＳＯ_２［Ｃ（Ｒ^９）_２］_０−６ＮＲ^ｋＲ^ｌ、Ｃ_１−３アルキルカルバモイル若しくはＣ_１−３ジアルキルカルバモイルであり；
Ｒ^ｅ及びＲ^ｆは、独立して、水素、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６アシル、ＳＯ_２Ｒ^８であり、Ｒ^８は、（ａ）Ｃ_１−６アルキル、（ｂ）Ｃ_１−６ハロアルキル、（ｃ）Ｃ_３−７シクロアルキル、（ｄ）Ｃ_３−７シクロアルキル−Ｃ_１−３アルキル、（ｅ）Ｃ_１−６アルコキシ−Ｃ_１−６アルキル又は（ｆ）ＳＯ_２［Ｃ（Ｒ^９）_２］_０−６ＮＲ^ｋＲ^ｌであり；
Ｒ^ｉ及びＲ^ｊは、（ｉ）独立して、水素、Ｃ_１−３アルキル又は（ＣＨ_２）_２−６ＮＲ^ｇＲ^ｈであるか、あるいは、（ｉｉ）それらが結合する窒素と一緒になって、（ＣＨ_２）_２Ｘ^５（ＣＨ_２）_２であり、Ｘ^５は、Ｏ又はＮＲ^ｋであり、そして、Ｒ^ｋは、水素、Ｃ_１−３アルキル、Ｃ_１−３アシル又はＣ_１−３アルキルスルホニルであり；
Ｒ^４は、水素、ＣＦ_３、ＣＨ_２ＣＦ_３、Ｃ_３−５シクロアルキル、ハロゲン、Ｃ_１−６アルコキシ、Ｃ_１−３ハロアルコキシ、ＣＨＲ^４ａＲ^４ｂ又はＣＲ^４ａＲ^４ｂＲ^４ｃであり、
式中、（ｉ）Ｒ^４ａ、Ｒ^４ｂ及びＲ^４ｃは、Ｃ_１−３アルキル、ＣＤ_３、Ｃ_１−２アルコキシ、Ｃ_１−２フルオロアルキル、Ｃ_１−３ヒドロキシアルキル、シアノ又はヒドロキシから独立して選択されるか；あるいは、
（ｉｉ）一緒になる場合、Ｒ^４ａ及びＲ^４ｂは、一緒になって、Ｃ_２−４アルキレンであり、そして、Ｒ^４ｃは、水素、Ｃ_１−３アルキル、Ｃ_１−２アルコキシ、ハロゲン、Ｃ_１−３ヒドロキシアルキル、シアノ又はＣ_１−２フルオロアルキルであるか、あるいは、Ｒ^４ａ及びＲ^４ｂは、それらが結合する炭素と一緒になって、３−オキセタニル又はテトラヒドロフラン−２−イルであり；
Ｒ^５は、出現ごとに独立して、水素、ハロゲン、Ｃ_１−６アルコキシ又はＣ_１−６アルキルであり；
Ｒ^８、Ｒ^ｇ及びＲ^ｈは、出現ごとに独立して、水素又はＣ_１−３アルキルであり；
Ｒ^ｋ及びＲ^ｌは、（ｉ）出現ごとに独立して、水素又はＣ_１−６アルキルであるか、あるいは、
（ｉｉ）それらが結合する窒素と一緒になって、Ｒ^ｋ及びＲ^ｌは、環状アミンを形成し；
ｎは、出現ごとに独立して、０〜３である］
に係る化合物又はその薬学的に許容しうる塩が提供される。 In one aspect of the invention, a compound of formula I:

[Where:
X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ;
X ¹ and X ² are N and X ³ and X ⁴ are CR ⁵ ;
X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N;
X ¹ and X ⁴ are N and X ² and X ³ are CR ⁵ ;
X ¹ , X ² , X ³ and X ⁴ are CR ⁵ ;
R ¹ represents (a) pyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro -Pyridazin-4-yl, 2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl, 6-oxo-1,6-dihydro- [1,2,4] triazin-5-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, 2-oxo-2 (H) -pyridin-1-yl, 6-oxo-6H-pyridazin-1-yl, 6-oxo A heteroaryl group selected from the group consisting of -6H-pyrimidin-1-yl and 2-oxo-2H-pyrazin-1-yl, wherein the heteroaryl is halogen, C _1-6 alkyl, C _1-3 Haloalkyl, C _1-6 hydro Optionally by xyalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 alkoxy, X ¹ (CH ₂ ) _1-6 CO ₂ H or X ^1- (CH ₂ ) _2-6 NR ^g R ^h Has been replaced, or
(B) 2-oxo-tetrahydro-pyrimidin-1-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2,6- Dioxo-tetrahydro-pyrimidin-1-yl, 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and 2,5-dioxo-imidazolidin-1-yl and 2,4-dioxo -A heterocyclic group selected from the group consisting of tetrahydro-pyrimidin-1-yl;
R ² is hydrogen, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy or halogen;
R ³ is (a) aryl,
(B) heteroaryl (wherein the aryl or the heteroaryl is hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 hydroxyalkyl, halogen, (CH ₂ ) _n NR ^c R ^d , Cyano, C _1-6 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, (CH ₂ ) _0-3 CO ₂ H, SO ₂ NH ₂ , C _1-6 alkylsulfinyl and C _1-6 Optionally independently substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl),
(C) NR ^a R ^b ,
(D) hydrogen,
(E) halogen,
Or (f) -X (R ⁷ ) [C (R ⁶ )] _2-6 NR ^e R ^f , where X is O or NR ⁷ , and
R ⁷ is hydrogen or C _2-4 alkyl;
R ⁶ is independently at each occurrence hydrogen, C _1-3 alkyl, or
Two R ⁶ residues on the same carbon are C _2-5 alkylene, or
Two R ⁶ residues on different carbons are C _1-4 alkylene);
R ^a and R ^b , together with the nitrogen to which they are attached, are independent of 1 to 3 groups independently selected from C _1-6 alkyl, halogen, or (CH ₂ ) _n NR ^e R ^f A substituted cyclic amine;
R ^c and R ^d are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 acyl, SO ₂ R ⁸ , R ⁸ is (a) C _1-6 alkyl (B) C _1-6 haloalkyl, (c) C _3-7 cycloalkyl, (d) C _3-7 cycloalkyl-C _1-3 alkyl, (e) C _1-6 alkoxy-C _1-6 alkyl Or (f) SO ₂ [C (R ⁹ ) ₂ ] _0-6 NR ^k R ^l , C _1-3 alkylcarbamoyl or C _1-3 dialkylcarbamoyl;
R ^e and R ^f are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 acyl, SO ₂ R ⁸ , R ⁸ is (a) C _1-6 alkyl (B) C _1-6 haloalkyl, (c) C _3-7 cycloalkyl, (d) C _3-7 cycloalkyl-C _1-3 alkyl, (e) C _1-6 alkoxy-C _1-6 alkyl Or (f) SO ₂ [C (R ⁹ ) ₂ ] _0-6 NR ^k R ^l ;
R ⁱ and R ^j are (i) independently hydrogen, C _1-3 alkyl or (CH ₂ ) _2-6 NR ^g R ^h , or (ii) together with the nitrogen to which they are attached. (CH ₂ ) ₂ X ⁵ (CH ₂ ) ₂ , X ⁵ is O or NR ^k , and R ^k is hydrogen, C _1-3 alkyl, C _1-3 acyl or C _1-3 alkylsulfonyl;
R ⁴ is hydrogen, CF ₃ , CH ₂ CF ₃ , C _3-5 cycloalkyl, halogen, C _1-6 alkoxy, C _1-3 haloalkoxy, CHR ^4a R ^4b or CR ^4a R ^4b R ^4c ,
In the formula, (i) R ^4a , R ^4b and R ^4c are independent of C _1-3 alkyl, CD ₃ , C _1-2 alkoxy, C _1-2 fluoroalkyl, C _1-3 hydroxyalkyl, cyano or hydroxy. Or choose;
(Ii) when taken together, R ^4a and R ^{4b taken} together are C _2-4 alkylene and R ^4c is hydrogen, C _1-3 alkyl, C _1-2 alkoxy, halogen, C _1-3 hydroxyalkyl, cyano or C _1-2 fluoroalkyl or R ^4a and R ^4b together with the carbon to which they are attached are 3-oxetanyl or tetrahydrofuran-2-yl ;
R ⁵ is independently for each occurrence hydrogen, halogen, C _1-6 alkoxy or C _1-6 alkyl;
R ⁸ , R ^g and R ^h are independently hydrogen or C _1-3 alkyl for each occurrence;
R ^k and R ^l are (i) independently for each occurrence hydrogen or C _1-6 alkyl, or
(Ii) together with the nitrogen to which they are attached, R ^k and R ^l form a cyclic amine;
n is 0 to 3 independently for each occurrence]
Or a pharmaceutically acceptable salt thereof.

  The compound represented by the general formula I may be a natural compound or a pharmaceutically acceptable salt thereof.

  The invention also provides a method for treating viral infections of hepatitis C virus (HCV) by administering a therapeutically effective amount of a compound according to Formula I to a patient in need thereof. The compound can be administered alone or co-administered with other antiviral compounds or immunomodulators.

  The present invention also provides a method for inhibiting HCV replication in cells by administering a compound according to Formula I in an effective amount that inhibits HCV.

  The present invention also provides a compound of formula I for treating a hepatitis C virus (HCV) viral infection or for preparing a medicament for treating a hepatitis C virus (HCV) viral infection. Use of a compound according to the invention is provided. The compound can be administered alone or co-administered with other antiviral compounds or immunomodulators.

  The present invention also provides the use of a compound of formula I for inhibiting HCV replication in a cell or for producing a medicament for inhibiting HCV replication in a cell.

  The present invention also provides a pharmaceutical composition comprising a compound according to formula I and at least one pharmaceutically acceptable carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the phrase “a” or “an” refers to one or more of the entities, eg, “a” compound refers to one or more compounds or at least one compound. Refers to one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

  The phrase “as defined herein above” refers to the broadest definition for each group as provided in the Summary of the Invention or the broadest claim. In all other embodiments provided below, substituents that may be present in each embodiment and that are not clearly defined retain the broadest definition provided in the Summary of the Invention.

  As used herein, the terms “comprise” and “comprising”, whether used in the claim transitional phrase or in the claim body, are non-limiting. It is interpreted as having a meaning. That is, the term is interpreted as synonymous with the phrase “having at least” or “including at least”. When used with respect to a process, the term “comprising” means that the process includes at least the listed steps, but may include additional steps. As used with respect to a compound or composition, the term “comprising” means that the compound or composition includes at least the listed features or elements, but may also include additional features or elements. means.

  As used herein, the term “independently” applies in any given case, regardless of the presence or absence of a variable having the same or different definition within the same compound. Indicates that Thus, in compounds where R ″ occurs twice and is defined as “independently carbon or nitrogen”, both R ″ can be carbon and both R ″ are nitrogen. Alternatively, one of R ″ can be carbon and the other can be nitrogen.

Any variable or moiety (eg, R ¹ , R ^4a , Ar, X ¹ or Het) appears more than once in any moiety or formula that represents or describes the compound used or claimed in the present invention If so, its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are allowed only when such compounds yield stable compounds.

The symbol "*" at the end of the bond or "---" drawn through the bond, respectively, refers to the point at which a functional group or other chemical moiety binds to the rest of the molecule that is part of it. So for example:

  A bond drawn into the ring system (as opposed to clearly binding to the apex) indicates that the bond can be bonded to any of the appropriate ring atoms.

  As used herein, the term “optional” or “optionally” means that the event or situation described subsequently may occur, but need not occur, and , Meaning that the description includes examples of when the event or situation occurs and examples of when it does not occur. For example, “optionally substituted” means that the optionally substituted moiety can contain hydrogen or a substituent.

  As used herein, the term “about” means approximately, about, around, or around. Where the term “about” is used in reference to a numerical range, it modifies the range by extending the upper and lower limits of the numerical value set forth. In general, the term “about” is used herein to modify a numerical value by a variation of 20% above and below the stated numerical value.

  As used herein, the description of a numerical range for a variable portion is intended to inform that the invention can be implemented with a variable portion equivalent to any of the values within that range. Thus, if the variable part is essentially discontinuous, the variable part can be equivalent to any integer value in the numerical range including the end of the range. Similarly, if the variable portion is essentially continuous, the variable portion can be equivalent to any real value in the numerical range including the end of the range. By way of example, a variable part described as having a value between 0 and 2 can be 0, 1 or 2 for a variable part that is essentially discontinuous, and for a variable part that is essentially continuous. , 0.0, 0.1, 0.01, 0.001 or any other real value.

  The compounds of formula I exhibit tautomerism. Tautomeric compounds can exist in more than one interconvertable species. Prototropic tautomers are formed by the transfer of covalently bonded hydrogen atoms between two atoms. In general, tautomers exist in equilibrium and attempts to isolate individual tautomers usually produce a mixture whose chemical and physical properties are consistent with the mixture of compounds. The position of the equilibrium depends on the chemical characteristics of the molecule. For example, for many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant; for phenol, the enol form is predominant. Common prototropic tautomers include keto / enol (—C (═O) —CH—⇔—C (—OH) ═CH—), amide / imidic acid (—C (═O) —NH—). ⇔-C (-OH) = N-) and amidine (-C (= NR) -NH-⇔-C (-NHR) = N-) tautomers. The latter two are particularly common with heteroaryls and heterocycles, and the present invention encompasses all tautomers of the present compounds.

  It will be apparent to those skilled in the art that some compounds of formula I may contain one or more chiral centers and thereby exist in more than one stereoisomer. Racemates of these isomers, mixtures containing many individual isomers and one enantiomer, as well as diastereomers when there are two chiral centers and some diastereomers in part Mixtures are included within the scope of the present invention. Furthermore, it will be apparent to those skilled in the art that substitution of the tropane ring can take either endo or exo configurations, and the present invention encompasses both configurations. The present invention includes all individual stereoisomers (eg, enantiomers), racemic mixtures or partially resolved mixtures of the compounds of Formula I, as appropriate, and individual tautomers thereof.

  The racemate can be used as is or can be resolved into its individual isomers. By splitting, a stereochemically pure compound or a mixture rich in one or more isomers can be obtained. Methods for separating isomers are known (see Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, to obtain either or both in a form that is substantially free of other isomers, i.e., optical purity> 95%, the individual isomers can be combined with 10-camphorsulfonic acid, camphoric acid, Forming diastereomeric salts with chiral acids of individual enantiomers, such as α-bromoshornoic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc., fractionally crystallizing and resolving the salt By liberating one or both of the bases, it can optionally be chemically separated from the mixture by repeating this process. Alternatively, the racemate is covalently bonded to a chiral compound (auxiliary) to produce diastereomers, which are separated by chromatography or fractional crystallization, after which the chiral auxiliary is chemically removed to give pure Enantiomers can be obtained.

  The compounds of formula I can contain basic centers and suitable acid addition salts are formed from acids which form non-toxic salts. Examples of inorganic acid salts are hydrochloride, hydrobromide, hydroiodide, chloride salt, bromide salt, iodide salt, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate Contains salt. Examples of organic acid salts include acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, cansylate, D and L-lactate, D and L- Tartrate, esylate, mesylate, malonate, orotate, glucoceptate, methyl sulfate, stearate, glucuronate, 2-naphthylate, tosylate, hibenzate, nicotine Acid salts, isethionates, malates, maleates, citrates, gluconates, succinates, saccharates, benzoates, esylates and pamoates. See Berge et al, J. Pharm. Sci., 1977 66: 1-19 and G. S. Paulekuhn et al. J. Med. Chem. 2007 50: 6665 for a description of suitable salts.

  Technical and scientific terms used herein have the meaning commonly understood by a person of ordinary skill in the art to which this invention pertains unless otherwise specified. Reference is made herein to various methods and materials known to those skilled in the art. Standard references describing general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill Companies Inc., New York (2001). Usually, the starting materials and reagents used in the preparation of these compounds are available from commercial sources such as Aldrich Chemical Co. or are prepared by methods known to those skilled in the art according to procedures described in the references. The materials, reagents and the like referred to in the following description and examples can be obtained from a vendor unless otherwise specified. General synthetic procedures are Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; RC LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) Vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40, which are well known to those skilled in the art. Would have been.

The term "isotopic substitutions" is used because only the isotopic composition to distinguish between different species ^{(IUPAC Compendium of Chemical Terminology 2 nd} Edition 1997). Isotope substitution may vary in the level of isotopic enrichment and / or the position of isotopic enrichment at one or more positions.

  Natural isotopic abundance changes occur in synthetic compounds depending on the source of chemical precursors used in the synthesis, and isotopic exchange can occur during synthesis. Therefore, the isotopic enrichment factor of each deuterium present at the site represented as the deuterated site is independent of deuteration at other sites, and some changes in the deuterium content outside the designated site. These changes can occur and these changes can result from the formation of isotopic substitutions, which are within the scope of the claimed compound. The deuterium enrichment factor for sites not represented as deuterium or “D” is less than 49.5%, typically much less than 49.5%, and more typically less than 20%. .

  Since the natural abundance of deuterium is 0.015%, changes in these naturally observed levels of deuterium will not have an effect on the observed biological properties of the compound. .

  Unless stated otherwise, when a position is expressed explicitly or implicitly as “H” or “hydrogen”, its isotopic ratio is assumed to have hydrogen at its natural abundance isotopic composition. . However, it is assumed that accidental changes may occur during the synthesis process.

  As used herein, the term “isotopic enrichment factor” means the ratio of the isotopic abundance of D at a particular position in a compound of the invention to the natural abundance of that isotope. In one embodiment of the invention, there is provided a compound according to formula I, wherein the isotopic enrichment factor of the tert-butyl moiety is at least 3300 (49.5%). In order to avoid ambiguity, in the case of tert-butyl, the isotopic enrichment factor refers to an assembly of three methyl groups, and the methyl groups are not evaluated independently.

  In other embodiments, for each deuterium present at a site represented as a potential deuterated site of the compound, at least 4000 (containing 60% deuterium), at least 4500 (67.5% deuterium). Containing), at least 5000 (75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 Provided are compounds according to Formula I having an isotopic enrichment factor of (97% deuterium containing), at least 6600 (99% deuterium containing) or at least 6633.3 (99.5% deuterium containing).

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^２、Ｘ^３及びＸ^４は、本明細書上記で定義したとおりである］
に係る化合物が提供される。 In one embodiment of the invention, Formula I:

[Wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein above]
A compound according to is provided.

In an embodiment of the invention, X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; alternatively, X ¹ and X ² are N and X ³ and X ⁴ are CR ⁵ ; alternatively, X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N; or X ¹ and X ⁴ are N And X ² and X ³ are CR ⁵ ; alternatively, X ¹ , X ² , X ³ and X ⁴ are CR ⁵ ; in particular, X ¹ is N, and X ² , X ³ , X ⁴ are CR ⁵ , or X ¹ and X ² are N, and X ³ and X ⁴ are CR ⁵ ;
R ¹ is (a) pyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro -Pyridazin-4-yl, 2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl, 6-oxo-1,6-dihydro- [1,2,4] triazin-5-yl, 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, 2-oxo-2 (H) -Pyridin-1-yl, 6-oxo-6H-pyridazin-1-yl, 6-oxo-6H-pyrimidin-1-yl; 2-oxo-2H-pyrazin-1-yl, especially pyridinyl, 2-oxo -1,2-dihydro-pyridin-3-yl , 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl selected from the group consisting of An aryl group, wherein the heteroaryl is halogen, C _1-6 alkyl, C _1-3 haloalkyl, C _1-6 alkoxy, X— (CH ₂ ) _1-6 CO ₂ H or X— (CH ₂ ) _{2 -6} NR ^g R ^h, in particular, _halogen, and optionally substituted by _{C 1-6} alkyl or _{C 1-6} alkoxy, or; (b) 2-oxo - tetrahydro - pyrimidin-1-yl, 2-oxo -Imidazolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2,6-dioxo-tetrahydro-pyrimidin-1-yl and A heterocyclic group selected from the group consisting of 2,5-dioxo-imidazolidin-1-yl;
R ² is hydrogen, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy or halogen;
R ³ is (a) aryl, (b) heteroaryl, (c) NR ^a R ^b , (d) hydrogen, (e) halogen, in particular (a) aryl, (c) NR ^a R ^b , (d ) Hydrogen, (e) halogen, wherein the aryl or heteroaryl is hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 hydroxyalkyl, halogen, (CH ₂ ) _n NR ^{cR d} , cyano, C _1-6 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, (CH ₂ ) _n CO ₂ H, SO ₂ NH ₂ , C _1-6 alkylsulfinyl and C _{1 -6} alkylsulfonyl, in particular _{halogen, (CH} 2) (wherein, n, a is 1) n ^NR c ^{R d} if with 1-3 substituents selected from the group consisting of Or it is substituted more independently, or ^{a (f) -X (R g)} [C (R 6)] p NR e R f, R 6 is, independently for each occurrence, hydrogen, _{C 1 -3} alkyl, or two R ⁶ residues on the same carbon are C _2-5 alkylene, or two R ⁶ residues on different carbons are C _1-4 R ^a and R ^b together with the nitrogen to which they are attached, together with the C _1-6 alkyl, halogen or (CH ₂ ) _n NR ^e R ^f , in particular (CH ₂ ) _n NR ^e R ^f (wherein n is 0 to 2) independently substituted cyclic amines; R ^c and R ^d are independently hydrogen, C _1-6 alkyl, C _1-6 Haloalkyl, C _1-6 acyl, C _1-6 sulfonyl, C _1-6 haloalkylsulfonyl, C _{3- 7} cycloalkylsulfonyl, C _3-7 cycloalkyl-C _1-3 alkyl-sulfonyl, C _1-6 alkoxy-C _1-6 alkylsulfonyl, —SO ₂ —NR ⁱ R ^j , C _1-3 alkylcarbamoyl or C _1-3 dialkylcarbamoyl, in particular R ^c is hydrogen and R ^d is C _1-6 sulfonyl; R ^e and R ^f are independently hydrogen, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 acyl, C _1-6 sulfonyl, C _1-6 haloalkylsulfonyl, C _3-7 cycloalkylsulfonyl, C _3-7 cycloalkyl-C _1-3 alkyl-sulfonyl, C _1-6 alkoxy _{-C 1-6 alkylsulfonyl,} be ^{-SO 2 -NR i R j; R} i and ^{R j} are independently (i), _{hydrogen, C 1-3} A Or a kill or _{^{(CH 2) 2-6 NR g R}} h, or together with the nitrogen to bind them _(ii), a ^{_{(CH 2) 2 X 5 (}} CH 2) 2, X 5 Is O or NR ^k and R ^k is hydrogen, C _1-3 alkyl, C _1-3 acyl or C _1-3 alkylsulfonyl; R ^g and R ^h are independently at each occurrence Hydrogen or C _1-3 alkyl, in particular, R ^e is hydrogen, and R ^f is C _1-6 sulfonyl;
R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-5 cycloalkyl, halogen, C _1-6 alkoxy, C _1-3 haloalkoxy or CR ^4a R ^4b R ^4c Wherein (i) R ^4a , R ^4b and R ^4c are independently selected from C _1-3 alkyl, C _1-2 alkoxy, C _1-2 fluoroalkyl, C _1-3 hydroxyalkyl, cyano or hydroxy Or (ii) when taken together, R ^4a and R ^4b are taken together are C _2-4 alkylene, and R ^4c is hydrogen, C _1-3 alkyl, C _{1- 2} alkoxy, _{halogen, C 1-3} hydroxyalkyl, or a cyano or _{C 1-2} fluoroalkyl, ^{or, R 4a} and ^{R 4b} together with the carbon to which they are attached, 3 An oxetanyl or tetrahydrofuran-2-yl, in particular, ^{R 4 is} a CR ^{4a R} 4b ^{R 4c, wherein,} R ^{4a, R 4b} and ^{R 4c} is methyl or, ^{R 4} is tri Fluoromethyl, 3,3,3-trifluoroethyl, or CR ^4a R ^4b R ^4c , wherein R ^4a , R ^4b and R ^4c are CH ₃ or CD ₃ ;
R ⁵ is independently for each occurrence hydrogen, halogen, C _1-6 alkoxy or C _1-6 alkyl;
X is independently O or NR ^g for each occurrence;
Provided is a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein n is independently 0 to 3 for each occurrence.

In another embodiment of the present invention, R ³ is (a) aryl or (b) heteroaryl, wherein said aryl or said heteroaryl is hydroxy, C _1-6 alkoxy, C _1-6. Alkyl, C _1-6 hydroxyalkyl, halogen, cyano, C _1-6 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, carboxyl, SO ₂ NH ₂ , C _1-6 alkylsulfinyl and C ₁ Provided are compounds according to formula I, optionally substituted independently with 1 to 3 substituents selected from the group consisting of _-6 alkylsulfonyl, wherein n is 0-3.

In another embodiment of the invention, X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; alternatively, X ¹ and X ² are N; A compound I according to the formula is provided wherein X ³ and X ⁴ are CR ⁵ . R ¹ is pyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and 2,4-dioxo- A heteroaryl group selected from the group consisting of 3,4-dihydro-2H-pyrimidin-1-yl, wherein said heteroaryl is optionally substituted by halogen, C _1-6 alkyl or C _1-6 alkoxy Yes. R ² is hydrogen or C _1-6 alkoxy, or R ¹ is 2-oxo-tetrahydro-pyrimidin-1-yl. R ³ is aryl, NR ^a R ^b , hydrogen or halogen, wherein the aryl is selected from the group consisting of halogen, (CH ₂ ) _n NR ^c R ^d (where n is 1). Optionally substituted independently with 1 to 3 substituents selected. R ^a and R ^b , together with the nitrogen to which they are attached, are independent of (CH ₂ ) _n NR ^e R ^f (where n is 0 to 2), C _1-6 alkyl or halogen. A cyclic amine optionally substituted with 1 to 3 groups selected as above. R ^e is hydrogen and R ^f is C _1-6 sulfonyl. R ^c is hydrogen and R ^d is C _1-6 sulfonyl. R ⁴ is trifluoromethyl, 3,3,3-trifluoroethyl or CR ^4a R ^4b R ^4c , where R ^4a , R ^4b and R ^4c are CH ₃ or CD ₃ . R ⁵ is independently for each occurrence hydrogen, halogen, C _1-6 alkoxy or C _1-6 alkyl. This embodiment includes pharmaceutically acceptable salts of the compounds encompassed herein.

In an embodiment of the invention, R ³ is (a) aryl or (b) heteroaryl, wherein said aryl or said heteroaryl is hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 hydroxyalkyl, halogen, cyano, C _1-6 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, carboxyl, SO ₂ NH ₂ , C _1-6 alkylsulfinyl and C _1-6 Provided are compounds according to formula I, optionally substituted independently with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, wherein n is 0-3.

In another embodiment of the invention, X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; R ³ is (a) at least (CH ₂ ) _n NR ^c Provided are compounds according to formula I, wherein phenyl is substituted at the 4-position by R ^d and n is 0 or (b) NR ^a R ^b . The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted. The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl or 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ and R ³ is phenyl substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d Wherein n is 0. A compound according to Formula I is provided.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; R ³ is phenyl substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d , N is 0, and R ⁴ is CR ^4a R ^4b R ^4c , wherein (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine, ^{Alternatively, R 4a} and ^{R 4b} are, together It turned to a _{C 2} alkylene, and is a ^{(b) R 4c} _{is, C 1-3 alkyl, C 1-2} alkoxy, _{halogen, C 1-3} hydroxyalkyl, cyano or _{C 1-2} fluoroalkyl, A compound according to Formula I is provided.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; R ³ is NR ^a R ^b ; and R ⁴ is CR ^4a R ^4b R ^4c In which (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine, or R ^4a and R ^4b together are C ₂ alkylene, and ^{(b) R 4c} _{is, C 1-3} alkyl C _1-2 alkoxy, _{halogen, C 1-3} hydroxyalkyl, cyano or _{C 1-2} fluoroalkyl, the compounds of the formula I are provided.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ; R ³ is NR ^a R ^b ; where NR ^a R ^b is taken together A cyclic amine substituted by (CH ₂ ) _n NR ^e R ^f , where n is 0-2; and R ^e and R ^f are independently hydrogen, C _{1- 6 alkyl, C 1-6} haloalkyl, _SO 2 ^{R 8, R 8} , _{(A) C 1-6} alkyl, _{(b) C 1-6} haloalkyl, _{(c) C 3-7} cycloalkyl, _{(d) C 3-7} cycloalkyl _{-C 1-3} alkyl, (e) _{C 1 -6} alkoxy-C _1-6 alkyl and R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine Or R ^4a and R ^{4b taken} together are C ₂ alkylene, and (b) R ^4c is C _1-3 alkyl, C _1-2 alkoxy, halogen, C _1-3 Compounds according to formula I are provided which are hydroxyalkyl, cyano or C _1-2 fluoroalkyl.

In another embodiment of the invention, R ¹ is 6-oxo-1,6-dihydro- [1,2,4] triazin-5-yl; X ¹ is N, and X ² , X ³ and X ⁴ are CR ⁵ and R ³ is phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , n is 0, A compound according to I is provided.

In another embodiment of the invention, R ¹ is 2-oxo-tetrahydro-pyrimidin-1-yl; X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ And R ³ is phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , and n is 0, a compound according to Formula I is provided.

In another embodiment of the invention, X ¹ and X ² are N, and X ³ and X ⁴ are CR ⁵ ; R ³ is (a) at least (CH ₂ ) _n NR ^c Provided are compounds according to formula I, wherein phenyl is substituted at the 4-position by R ^d and n is 0 or (b) NR ^a R ^b .

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl or 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ and X ² are N, X ³ and X ⁴ are CR ⁵ and R ³ is phenyl substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d Wherein n is 0 or 1 is provided.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl or 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ and X ² are N, X ³ and X ⁴ are CR ⁵ and R ³ is phenyl substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d Wherein n is 0 or 1 is provided.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ and X ² are N, X ³ and X ⁴ are CR ⁵ and R ³ is phenyl substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d N is 0 and R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine ^{or, R 4a} and R ^b, taken together, a _{C 2} alkylene, and, ^{(b) R 4c} _{is C 1-3 alkyl, C 1-2} alkoxy, _{halogen, C 1-3} hydroxyalkyl, cyano or _{C 1-2} Compounds according to formula I are provided that are fluoroalkyl.

In another embodiment of the present invention 2-oxo-1,2-dihydro-, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy. Pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl; X ¹ and X ² are N and X ³ and X ⁴ are CR ⁵ ; R ³ is NR ^a R ^b ; where NR ^a R ^b is taken together A cyclic amine substituted by (CH ₂ ) _n NR ^e R ^f , where n is 0-2; and R ^e and R ^f are independently hydrogen, C _{1- 6 alkyl, C 1-6} haloalkyl, _SO 2 ^{R 8,} R But, _{(a) C 1-6} alkyl, _{(b) C 1-6} haloalkyl, _{(c) C 3-7} cycloalkyl, _{(d) C 3-7} cycloalkyl _{-C 1-3} alkyl, (e) C _1-6 alkoxy-C _1-6 alkyl and R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine Or R ^4a and R ^{4b taken} together are C ₂ alkylene, and (b) R ^4c is C _1-3 alkyl, C _1-2 alkoxy, halogen, C _1- Compounds according to formula I are provided which are ₃ hydroxyalkyl, cyano or C _1-2 fluoroalkyl.

In another embodiment of the present invention, there is provided a compound according to formula I, wherein X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N.

In another embodiment of the invention, X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N; R ³ is (a) at least (CH ₂ ) _n NR ^c It is phenyl substituted at the 4-position by R ^d , and n is 0 or (b) NR ^a R ^b . The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted. The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted.

In another embodiment of the present invention, there is provided a compound according to formula I, wherein X ¹ and X ⁴ are N and X ² and X ³ are CR ⁵ .

In another embodiment of the present invention, X ¹ and X ⁴ are N and X ² and X ³ are CR ⁵ ; R ³ is (a) at least (CH ₂ ) _n NR ^c Provided are compounds according to formula I, wherein phenyl is substituted at the 4-position by R ^d and n is 0 or (b) NR ^a R ^b . The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted. The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted.

In another embodiment of the present invention, there is provided a compound according to formula I, wherein X ¹ , X ² , X ³ and X ⁴ are CR ⁵ .

In another embodiment of the invention, X ¹ , X ² , X ³ and X ⁴ are CR ⁵ ; R ³ is (a) substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d There is provided a compound according to formula I, wherein n is 0 or (b) NR ^a R ^b . The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted. The phrase “phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d ” refers to (i) the unsubstituted position may be optionally further substituted.

In another embodiment of the present invention, X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ and R ¹ is 2,6-dioxo-tetrahydro-pyrimidine-1 -Yl, 2,5-dioxo-imidazolidin-1-yl or 2,4-dioxo-tetrahydro-pyrimidin-1-yl; and R ³ is (a) at least (CH ₂ ) _n NR ^c R Provided are compounds according to formula I, wherein phenyl is substituted at the 4-position by ^d and n is 0 or (b) NR ^a R ^b .

  In another embodiment of the present invention, compounds selected from I-1 to I-60 of Table I and II-1 to II-2 of Table II, in particular I-1 to I-33 of Table I, In particular, compounds selected from I-1 to I-31 of Table I are provided.

In another embodiment of the invention, a method of treating HCV infection in a patient in need thereof, comprising a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , There is provided a method comprising administering a compound according to X ¹ , X ² , X ³ and X ⁴ as defined herein above.

In another embodiment of the invention, a method of treating HCV infection in a patient in need thereof, comprising a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein above) and at least one immune system modulator and / or at least one antiviral agent that inhibits HCV replication Is provided.

In another embodiment of the invention, a method of treating a disease caused by HCV in a patient in need thereof, comprising a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein above) and at least one immunity selected from interferon, interleukin, tumor necrosis factor or colony stimulating factor A method is provided that comprises co-administering with a system modulating agent.

In another embodiment of the invention, a method of treating HCV infection in a patient in need thereof, comprising a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , A method is provided comprising co-administering a compound according to X ¹ , X ² , X ³ and X ⁴ as defined herein above and an interferon or a chemically derivatized interferon.

In another embodiment of the invention, a method of treating HCV infection in a patient in need thereof, comprising a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein above) and an HCV protease inhibitor, another HCV polymerase inhibitor, an HCV helicase inhibitor, an HCV primase inhibitor And a co-administration with another antiviral compound selected from the group consisting of an HCV fusion inhibitor.

In another embodiment of the present invention, a therapeutically effective amount of Formula I, wherein R ¹ , R ² , R ³ , mixed with at least one pharmaceutically acceptable carrier, diluent or excipient. ^{R 4, X 1, X 2} , X 3 and X ^4, a compound represented by the is) as defined herein above, by delivering, provides a method for inhibiting viral replication in a cell Is done.

In another embodiment of the invention, for the treatment of HCV infection, Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are As defined hereinabove) is provided.

In another embodiment of the invention, a compound of formula I (wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X, X) for the manufacture of a medicament for treating HCV infection ³ and X ⁴ are as defined herein above) is provided.

In another embodiment of the invention, for the treatment of HCV infection, Formula I, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are There is provided the use of a compound according to (as defined herein above) and at least one immune system modulator and / or at least one antiviral agent that inhibits the replication of HCV.

In another embodiment of the invention, a compound of formula I (wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X, X) for the manufacture of a medicament for treating HCV infection ³ and X ⁴ are as defined herein above) and at least one immune system modulator and / or use of at least one antiviral agent that inhibits HCV replication is provided. .

In another embodiment of the present invention, Formula I wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ are as defined herein above. There is provided a composition comprising a compound according to (a) and at least one pharmaceutically acceptable carrier, diluent or excipient.

As used herein, the term “alkyl”, whether used alone or in combination with other groups, is a monovalent unbranched or branched chain containing 1 to 10 carbon atoms. Means a chain saturated hydrocarbon residue. The term “lower alkyl” means a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. “C _1-6 alkyl” as used herein refers to an alkyl composed of 1 to 6 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, tert-butyl, neopentyl, hexyl and octyl. Any carbon hydrogen bond can be replaced with a carbon deuterium bond without departing from the scope of the invention.

  The definitions set forth herein supplement the formation of chemically related combinations such as “heteroalkylaryl”, “haloalkylheteroaryl”, “arylalkylheterocyclyl”, “alkylcarbonyl”, “alkoxyalkyl”, etc. Can be done. When the term “alkyl” is used as a suffix following another term such as “phenylalkyl” or “hydroxyalkyl”, it is selected from other specifically named groups 1 It is intended to refer to an alkyl group as defined above that is substituted with two substituents. Thus, for example, “phenylalkyl” refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. “Alkylaminoalkyl” is an alkyl group having 1-2 alkylamino substituents. “Hydroxyalkyl” means 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxy Including propyl. Thus, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups as defined below. The term-(Ar) alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero) aryl or (hetero) aryl refers to either an aryl or heteroaryl group.

The term “alkylene” as used herein, unless otherwise specified, is a divalent straight chain saturated hydrocarbon group of 1 to 10 carbon atoms (eg, (CH ₂ ) _n ) or 2 to 10 number of divalent branched chain saturated hydrocarbon group having carbon atoms (e.g., -CHMe- or _{-CH 2 CH (i-Pr)} CH 2 -) means. C _0-4 alkylene refers to a divalent linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms (or in the case of C ₀ , the alkylene group is omitted). Except in the case of methylene, the empty valences of the alkylene group are not bonded to the same atom. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

As used herein, the term “alkoxy” refers to an —O-alkyl group, where alkyl is as defined above, methoxy, ethoxy, n-propyloxy, i— Propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy and the like, and further includes these isomers. “Lower alkoxy” as used herein refers to an alkoxy group having a “lower alkyl” group as defined above. “C _1-10 alkoxy” as used herein refers to —O-alkyl wherein alkyl is C _1-10 .

  As used herein, the term “haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one, two, three or more hydrogen atoms are replaced with a halogen. . Examples include 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl. As used herein, the term “fluoroalkyl” refers to a haloalkyl moiety in which the halogen is fluorine.

  As used herein, the term “haloalkoxy” refers to the group —OR, where R is haloalkyl as defined herein. As used herein, the term “haloalkylthio” refers to the group —SR, wherein R is haloalkyl as defined herein.

As used herein, the term “cycloalkyl” means a saturated carbocyclic ring containing 3 to 8 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. To do. “C _3-7 cycloalkyl” as used herein refers to a cycloalkyl composed of 3 to 7 carbons in a carbocyclic ring.

  As used herein, the term “halogen” or “halo” means fluorine, chlorine, bromine or iodine.

As used herein, the terms “hydroxyalkyl” and “alkoxyalkyl” as used herein refer to replacement of 1 to 3 hydrogen atoms on different carbon atoms with a hydroxyl or alkoxy group, respectively. Means an alkyl group as defined; C _1-3 alkoxy _{-C 1-6} alkyl moiety, 1 to 3 hydrogen atoms are substituted with _{C 1-3} alkoxy, and _{C 1-6} alkyl substituent the point of attachment of the alkoxy is an oxygen atom Point to.

  As used herein, the terms “alkoxycarbonyl” and “aryloxycarbonyl” have the formula —C (═O) OR where R is alkyl or aryl, respectively, and alkyl and aryl are , As defined herein).

As used herein, the term “cyano” refers to a carbon attached to a nitrogen with a triple bond, ie, —C≡N. As used herein, the term “nitro” refers to the group —NO ₂ . As used herein, the term “carboxy” refers to the group —CO ₂ H.

  The term oxo refers to a double bond oxygen (═O), ie a carbonyl group.

As used herein, the term “acyl” (or “alkanoyl”) is of the formula —C (═O) R, where R is hydrogen or lower alkyl as defined herein. Means group. As used herein, the term “alkylcarbonyl” refers to a group of formula C (═O) R, wherein R is alkyl as defined herein. The term C _1-6 acyl or “alkanoyl” refers to a group —C (═O) R containing from 1 to 6 carbon atoms. A C ₁ acyl group is a formyl group with R═H, and a C ₆ acyl group refers to hexanoyl when the alkyl chain is unbranched. As used herein, the term “arylcarbonyl” or “aroyl” refers to a group of the formula C (═O) R, where R is an aryl group; The term “benzoyl” refers to an “arylcarbonyl” or “aroyl” group where R is phenyl.

As used herein, the term “cyclic amine” refers to a saturated carbocycle containing from 3 to 6 carbon atoms as defined above, wherein at least one carbon atom is N, Substituted with a heteroatom selected from the group consisting of O and S. For example, piperidine, piperazine, morpholine, thiomorpholine, di-oxo-thiomorpholine, pyrrolidine, pyrazoline, imidazolidine, azetidine, wherein the cyclic carbon atom consists of halogen, hydroxy, phenyl, lower alkyl, lower alkoxy It is optionally substituted with one or more substituents selected from the group, or both two hydrogen atoms on the carbon are replaced with oxo (= O). When the cyclic amine is piperazine, one nitrogen atom can be optionally substituted with C _1-6 alkyl, C _1-6 acyl, C _1-6 alkylsulfonyl.

As used herein, the terms “alkylsulfonyl” and “arylsulfonyl” have the formula —S (═O) ₂ R, where R is alkyl or aryl, respectively, and alkyl and aryl are As defined in the specification). As used herein, the term C _1-3 alkylsulfonylamide refers to the group RSO ₂ NH—, where R is a C _1-3 alkyl group as defined herein. The terms C _1-6 haloalkylsulfonyl, C _3-7 cycloalkylsulfonyl, C _3-7 cycloalkyl-C _1-3 alkylsulfonyl or C _1-6 alkoxy-C _1-6 alkylsulfonyl are the compounds S (═O) ₂ R wherein R is C _1-6 haloalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl and C _1-6 alkoxy-C _1-6 alkyl, respectively. ).

As used herein, the term “sulfamoyl” refers to the group —S (O) ₂ NH ₂ . As used herein, the terms “N-alkylsulfamoyl” and “N, N-dialkylsulfamoyl” refer to the group —S (O) ₂ NR′R ″ where R ′ and R ″ Is hydrogen and lower alkyl, and R ′ and R ″ are each independently lower alkyl). Examples of N-alkylsulfamoyl substituents include, but are not limited to, methylaminosulfonyl, isopropylaminosulfonyl. Examples of N, N-dialkylsulfamoyl substituents include, but are not limited to, dimethylaminosulfonyl, isopropyl-methylaminosulfonyl.

As used herein, the term “carbamoyl” refers to the group —CONH ₂ . The prefixes “N-alkylcarbamoyl” and “N, N-dialkylcarbamoyl” refer to the group CONHR ′ or CONR′R ″, respectively, wherein R ′ and R ″ groups are independently defined herein. Defined alkyl). The prefix “N-arylcarbamoyl” refers to the group CONHR ′, where R ′ is an aryl group as defined herein.

As used herein, the term “benzyl” refers to a C ₆ H ₅ CH ₂ group, where the phenyl ring is hydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, unless otherwise specified. Alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonyl Independently from amino, arylsulfonylamino, carbamoyl, alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino One or more substituents selected, preferably may be optionally substituted with 1 to 3 substituents.

  As used herein, the term “heteroaryl” refers to “pyridinyl”, “pyrazinyl” and “pyridazinyl” rings without additional definition or limitation. The term “pyridine” (“pyridinyl”) refers to a 6-membered aromatic heterocycle having one nitrogen atom. The terms “pyrimidine” (“pyrimidinyl”), “pyrazine” (“pyrazinyl”) and “pyridazine” (“pyridazinyl”) refer to the relationship in which two nitrogen atoms are 1, 3, 1, 4, and 1, 2, respectively. Refers to a 6-membered non-fused aromatic heterocycle arranged in The name of each group is shown in parentheses.

  The terms “oxetane” (oxetanyl), “tetrahydrofuran” (tetrahydrofuranyl) and “tetrahydropyran” (tetrahydropyranyl) are respectively 4-, 5- and 6-membered non-fused heterocycles containing one oxygen atom. Refers to a cyclic ring.

  As used herein, the term “aryl” refers to phenyl.

The term (i) 3-oxo-3,4-dihydro-pyrazin-2-yl, (ii) 3-oxo-2,3-dihydro-pyridazin-4-yl, (iii) 2-oxo-1,2- Dihydro-pyrimidin-4-one-5-yl, (iv) 2-oxo-1,2-dihydro-pyridin-3-yl, (v) 6-oxo-1,6-dihydro- [1,2,4 ] Triazin-5-yl and (vi) 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl refer to the following moieties:

The term (viii) 2-oxo-tetrahydro-pyrimidin-1-yl, (ix) 2-oxo-imidazolidin-1-yl, (x) 2-oxo-piperidin-1-yl, (xi) 2-oxo- Pyrrolidin-1-yl, (xii) 2,6-dioxo-tetrahydro-pyrimidin-1-yl and (xiii) 2,5-dioxo-imidazolidin-1-yl refer to the following moieties:

The terms (xiv) 2-oxo-2 (H) -pyridin-1-yl, (xv) 6-oxo-6H-pyridazin-1-yl, (xvi) 6-oxo-6H-pyrimidin-1-yl, ( xvii) 2-oxo-2H-pyrazin-1-yl and (xviii) 2,4-dioxo-tetrahydro-pyrimidin-1-yl refer to the following moieties:

  The compounds of the present invention and isomers thereof and pharmaceutically acceptable salts thereof are also used in combination with each other, and include, but are not limited to, interferon, pegylated interferon, ribavirin, protease inhibitor, polymerase inhibitor, small molecule Others including the group consisting of interfering RNA compounds, antisense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory drugs, antibiotics, antiviral agents and anti-infective compounds When used in combination with biologically active agents, it is useful for the treatment and prevention of viral infections in living hosts, particularly hepatitis C infections and diseases. Such combination therapies may also cause the compounds of the present invention to be combined with other pharmaceutical agents or enhancers such as ribavirin and related compounds, amantadine and related compounds such as interferon-α, interferon-β, interferon γ, etc. Supplying various interferons, as well as any other form of interferon, such as pegylated interferon, simultaneously or sequentially. Furthermore, the combination of ribavirin and interferon can be administered as an additional combination therapy with at least one compound of the invention.

  In one embodiment, the compounds of the invention according to formula I are used in combination with other active therapeutic ingredients or agents to treat patients with HCV virus infection. According to the present invention, the active therapeutic ingredient used in combination with the compound of the present invention can be any drug that exhibits a therapeutic effect when used in combination with the compound of the present invention. For example, active agents used in combination with the compounds of the present invention include interferons, ribavirin analogs, HCV NS3 protease inhibitors, HCV polymerase nucleoside inhibitors, HCV polymerase non-nucleoside inhibitors and other agents for treating HCV. It can be a drug, or a mixture thereof.

  Examples of nucleoside inhibitors of NS5b polymerase include, but are not limited to, NM-283, Valopicitabine, R1626, PSI-6130 (R1656), IDX184 and IDX102 (Idenix) BILB1941.

  Examples of non-nucleoside NS5b polymerase inhibitors include, but are not limited to, HCV-796 (ViroPharma and Wyeth), MK-0608, MK-3281 (Merck), NM-107, R7128 (R4048), VCH-759, GSK625433 and GSK625433 (Glaxo), PF-868554 (Pfizer), GS-9190 (Gilead), A-837093 and A848837 (Abbot Laboratories), ANA598 (Anadys Pharmaceuticals); GL100597 (GNLB / NVS), VBY708 (ViroBay), benzimidazole derivatives (H. Hashimoto et al., International Publication No. 01/47833, H. Hashimoto et al., International Publication No. 03/000254, PL Beaulieu et al., International Publication No. 03/020240 A2; PL Beaulieu et al., US Patent No. 6,448,281 B1; PL Beaulieu et al., International Publication No. 03/007945 A1), Benzo-1,2,4-thiadiazine Derivatives (D. Dhanak et al., International Publication No. 01/85172 A1, 5/10/2001 application; D. Chai et al., International Publication No. 2002098424, 6/7/2002 application, D. Dhanak et al., International Publication No. 03/037262 A2, 10/28/2002 application; KJ Duffy et al., International Publication No. 03/099801 A1, 5/23/2003 application, MG Darcy et al., International Publication No. 20030359356, 10 / 28/2002 application; D.Chai et al., International Publication No. 2004052312, 6/24/2004 application, D.Chai et al., International Publication No. 2004052313, 12/13/2003 application; DM Fitch et al., International Publication Gazette No. 2004058150, 12/11/2003 application; DK Hutchinson et al., International Publication No. 2005019191, 8/19/2004 application; JK Pratt et al., International Publication No. 2004/041818 A1, 10/31/2003 application) 1,1-dioxo-4H-benzo [1,4] thiazin-3-yl derivatives (JF Blake et al., US Patent Publication No. US20060252785) and 1,1-dioxo-benzo [d] isothiazol-3-yl Compound (JF Blake , Including US Patent Publication No. 2006040927).

  Examples of HCV NS3 protease inhibitors include, but are not limited to, SCH-503034 (Schering, SCH-7), VX-950 (telaprevir, Vertex), BILN-2065 (Boehringer-Ingelheim), BMS-605339 (Bristol Myers Squibb) And ITMN-191 (Intermune).

  Examples of interferons include, but are not limited to, pegylated rIFN-α-2b, pegylated rIFN-α-2a, rIFN-α-2b, rIFN-α-2a, consensus IFN-α (infergen), ferron, Rareferon, intermax-α, r-IFN-β, Infergen and Actimune, IFN-ω in combination with DUROS, Albuferon, Locteron, Albuferon, Leviv, Oral interferon-α, IFN-α- 2b Contains XL, AVI-005, PEG-infagen and pegylated IFN-β.

  Ribavirin analogs and ribavirin prodrug viramidine (Talavivirin) are administered in conjunction with interferon to suppress HCV.

Commonly used abbreviations include: acetyl (Ac), aqueous (aq.), Atmospheric pressure (Atm), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or Boc anhydride (BOC ₂ O), benzyl (Bn), butyl (Bu), chemical abstract registration number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyldiimidazole (CDI), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7- Ene (DBU), N, N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), azodicar Diethyl borate (DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), diisopropylethylamine (DIPEA), N, N-dimethylacetamide (DMA), 4-N, N-dimethyl Aminopyridine (DMAP), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl (Et), ethanol (EtOH), 1,1′-bis- (diphenylphosphino) ethane (dppe), 1 , 1′-bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), ethyl acetate (EtOAc), 2-ethoxy-2H-quinoline- 1-carboxylic acid ethyl ester EEDQ), diethyl ether _{(Et 2 O), O- (} 7- azabenzotriazole-1-yl) -N, N, N'N'- tetramethyluronium hexafluorophosphate (HATU), acetic acid (HOAc) , 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), isopropanol (IPA), methanol (MeOH), melting point (mp), MeSO _2- (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl tert-butyl ether (MTBE), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), phenyl (Ph), propyl (Pr), isopropyl (i-Pr), pounds per square inch (psi) . Pyridine (pyr), room temperature (rt or RT), satd (saturated), tert-butyldimethylsilyl or _{t-BuMe 2 Si (TBDMS)} , triethylamine (TEA or _Et 3 N), triflate or _CF 3 SO ₂ - (Tf), trifluoroacetic acid (TFA), O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium tetrafluoroboric acid (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), tetramethylethylenediamine (TMEDA), trimethylsilyl or _Me 3 Si (TMS), p- toluenesulfonic acid monohydrate (TsOH or _{pTsOH), 4-Me-C} 6 H 4 SO 2 - or tosyl ( Ts), N-urethane-N-carboxyanhydride (UNCA). Conventional nomenclature, including the prefix normal (n-), iso (i-), secondary (sec-), tertiary (tert-) and neo (neo-) are used in the alkyl moiety. The case has its customary meaning (J. Rigaudy and DP Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

  Examples of representative compounds encompassed by the present invention and within the scope of the present invention are provided in the following table. These examples and preparations below are provided to enable those skilled in the art to more clearly understand and to practice the present invention. It should be understood that these are not intended to limit the scope of the invention, but are merely illustrative and exemplary.

  In general, the nomenclature used in this application is the Beilstein Institute computer system AUTONOM ™ v. For creating an IUPAC systematic nomenclature. Based on 4.0. If there is a difference between the drawn structure and the names given to the structure, the drawn structure shall prevail. Furthermore, if the stereochemistry of a structure or part of a structure is not indicated, for example, by a bold or dotted line, the structure or part of the structure is taken to encompass all of its stereoisomers.

The following numbering system is used herein.

  The compounds in Table II illustrate additional compounds within the scope of this specification.

  The compounds of the present invention can be made by a variety of methods described in the exemplary synthetic reaction schemes shown and described below. Starting materials and reagents used in the preparation of these compounds are usually available from vendors such as Aldrich Chemical Co. or by methods known to those skilled in the art according to the procedures described in the references below. Prepared: Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; RC LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I Fleming (Eds.) Vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and / or ganic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely to illustrate some of the ways in which the compounds of the present invention can be synthesized, and various modifications can be made to these synthetic reaction schemes, which will be apparent to those skilled in the art. It will be suggested to refer to the disclosure contained in.

  The starting materials and intermediates in the synthetic reaction scheme can be isolated and purified using conventional techniques such as, but not limited to, filtration, distillation, crystallization, chromatography, etc., if desired. Such materials can be characterized using conventional means, including physical constants and spectral data.

  Unless stated otherwise, the reactions described herein are preferably carried out at atmospheric pressure and under an inert atmosphere, from about −78 ° C. to about 150 ° C., more preferably from about 0 ° C. to about 125 ° C., most preferably And conveniently, it is carried out at about room temperature (or ambient temperature), for example, a reaction temperature of about 20 ° C.

  Some compounds in the schemes below are described with generalized substituents; however, one skilled in the art will readily appreciate that the nature of the R group can be modified to yield various compounds contemplated by the present invention. Will understand. Furthermore, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims.

本発明に包含されるキノリン誘導体は、Skraupキノリン合成の改変により調製される。式中、アニリンＡ−２と１，２，２−トリブロモアクロレイン（Ａ−３）との酸触媒縮合により、ブロモキノリンＡ−４が得られる。縮合は、典型的には、発明の概要で提供されるように、Ｒ^１がヘテロアリール部分又は最終的に前記ヘテロアリール部分に変換されるその保護形態のアニリンで行われる。Ｒ^２がヘテロアリールであるＡ−２を与える、ヘテロアリール部分の導入は、オルトブロモアニリンＡ−１とヘテロアリールボロン酸とのパラジウム触媒カップリングにより容易に達成される。

The quinoline derivatives encompassed by the present invention are prepared by modification of the Skraup quinoline synthesis. In the formula, bromoquinoline A-4 is obtained by acid-catalyzed condensation of aniline A-2 and 1,2,2-tribromoacrolein (A-3). The condensation is typically carried out with an aniline in its protected form in which R ¹ is converted to a heteroaryl moiety or ultimately said heteroaryl moiety, as provided in the Summary of the Invention. Introduction of a heteroaryl moiety, giving A- ² where R ² is heteroaryl, is readily accomplished by palladium-catalyzed coupling of orthobromoaniline A-1 and heteroaryl boronic acid.

  Boronic acids useful for the preparation of the compounds of the present invention include, but are not limited to, 2-methoxy-pyridin-3-ylboronic acid (CASRN 163105-90-6), 2-benzyloxy-3-pyridineboronic acid, 2- Oxo-1,2-dihydropyridine-3-boronic acid (CASRN 951655-49-5), 5-fluoro-2-methoxy-3-pyridineboronic acid (CASRN 957120-32-0), 2-methoxy-6-methyl -Pyridin-3-ylboronic acid (CASRN 1000802-75-4), 5-chloro-2-methoxy-pyridin-3-ylboronic acid (CASRN 943153-22-8), 2,6-dimethoxypyridin-3-ylboronic acid (115, CASRN 221006-70-8), B- (2,3-dihydro-3-oxo-4-pyridazinyl) -boronic acid (Example 16) or 2,4-dioxo-1,2,3,4 -Tetrahydropyrimidin-5-ylboronic acid (CASRN 70523-22-7) No. One skilled in the art will recognize that boronic acids and boronic esters, such as 4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl groups, can be used interchangeably in Suzuki coupling. You will recognize. The oxo group can be masked as an alkyl ether, which requires a subsequent dealkylation step to give the oxo group. This is easily done by heating in HBr / HOAc.

Following the synthesis of quinoline, a 3-aryl substituent is directly introduced as R ³ by a second Suzuki coupling with an aryl boronic acid such as 4- (methanesulfonamido) -phenylboronic acid or 4-nitrophenylboronic acid. A-5 is obtained. Those skilled in the art will appreciate the use of a wide range of arylboronic acids that provide great flexibility with regard to the order of functional group transformations required and the nature of the R ³ substituent.

Skraup縮合は、また、ブロモアニリンで行って、Ｒ^１が臭素であるＡ−４を与えることができ、ヘテロアリールのＲ^１置換基を導入するSuzukiカップリングは、その後、キノリンで行われる。実施例１３で示されるように、好ましいカップリングは、３位で行われる。８−ブロモ誘導体（Ｂ−１）の有用性は、さらなる合成フレキシビリティを与えられる。８−ブロモキノリン（Ａｒは、反応条件下で反応しない）のメタル化により、ボロン酸をキノリン環（Ｂ−２）に導入することができ、これを、ハロゲン又はトリフルオロメチルスルホニルオキシ置換基により置換されているヘテロアリール化合物、例えば、２−クロロ−３−メトキシ−ピラジン（CASRN 40155-28-0）とSuzukiカップリングさせることができ、これが脱メチル化され、３−オキソ−３，４−ジヒドロ−ピラジン−２−イル部分を与える。

The Skraup condensation can also be performed with bromoaniline to give A-4 where R ¹ is bromine, and the Suzuki coupling to introduce the heteroaryl R ¹ substituent is then performed with quinoline. As shown in Example 13, the preferred coupling is in the 3 position. The usefulness of the 8-bromo derivative (B-1) provides additional synthetic flexibility. Boronic acid can be introduced into the quinoline ring (B-2) by metalation of 8-bromoquinoline (Ar does not react under the reaction conditions), which can be converted by halogen or trifluoromethylsulfonyloxy substituents. It can be Suzuki coupled with a substituted heteroaryl compound, for example 2-chloro-3-methoxy-pyrazine (CASRN 40155-28-0), which is demethylated to give 3-oxo-3,4- A dihydro-pyrazin-2-yl moiety is provided.

Suzuki reaction involves boronic acid (R—B (OH) ₂ ) (where R is aryl or vinyl) and aryl or vinyl halide or triflate (R′Y, where R ′ = aryl or vinyl) Y = palladium-catalyzed coupling with halide or —OSO ₂ CF ₃ ) to give compound RR ′. Typical catalysts include Pd (PPh ₃ ) ₄ , Pd (OAc) ₂ and PdCl ₂ (dppf). PdCl ₂ (dppf) can be used to _couple primary alkylborane compounds with aryl or vinyl halides or triflates without β-elimination. Highly active catalysts have been described (eg JP Wolfe et al., J. Am. Chem. Soc. 1999 121 (41): 9550-9561 and AF Littke et al., J. Am. Chem. Soc. 2000 122 (17): 4020-4028). The reaction can be carried out in various organic solvents such as toluene, THF, dioxane, DCE, DMF, DMSO and MeCN, in aqueous solvents and under two-phase conditions. Typically, the reaction is conducted at about room temperature to about 150 ° C. Additives (eg, CsF, KF, TlOH, NaOEt and KOH) often promote coupling. The Suzuki reaction has many parameters including palladium source, ligand, additives and temperature, and optimal conditions sometimes require optimization of the parameters for the target reactant pair. AF Littke et al. Described the conditions for Suzuki cross-coupling with high yield arylboronic acid using Pd ₂ (dba) ₃ / P (tert-bu) ₃ at room temperature and Pd at room temperature. Disclose conditions for aryl and vinyl triflate cross-coupling using (OAc) ₂ / P (C ₆ H ₁₁ ) ₃ . JP Wolf et al., Supra, disclose efficient conditions for Suzuki cross-coupling using Pd (OAc) ₂ / o- (di-tert-butylphosphino) biphenyl or o- (dicyclohexylphosphino) biphenyl. ing. One skilled in the art will be able to determine the appropriate conditions without undue experimentation.

一般式Ｉの化合物（式中、Ｒ^１は、炭素−窒素結合により結合した複素環である）は、銅又はパラジウム触媒アリールアミノ化反応により調製することができる。アリールアミノ化の方法は、これまでに記載されている。２−オキソ−テトラヒドロ−ピリミジン−１−イル又は２−オキソ−イミダゾリジン−１−イル置換基の導入は、ブロモキノリンと１，３−ジアミノ−プロパン（工程１）又は１，２−ジアミノ−エタン（D. Ma et al., Org. Lett. 2003 5(14):2453）とのＣｕＩ触媒アリールアミノ化、その後の、カルボニルジイミダゾールを用いた分子内環化（工程２）により達成することができる。あるいは、複素環式環を、一級アミンＣ−４から合成することができる。ハロゲンの置換により一級アミンをアリール環に導入する（工程３）、多くの方法がこれまでに記載されている（J.P. Wolfe et al. Tetrahedron Lett. 1997 38(36):6367; C.-Z. Tao et al., Tetrahedron Lett. 2008 49:70; Q. Shen and J.F. Hartwig, J. Am. Chem. Soc. 2006 128:10028; S. S. Surry and S. L. Buchwald, J. Am. Chem. Soc. 2007 129:10354）。５−ブロモ−ペンタン酸（工程５）又は４−ブロモ−酪酸を用いたＣ−４のアシル化、その後の、分子内環化（工程６）により、それぞれ、ピペリドン（Ｃ−８、ｎ＝１）及びピロリドン（Ｃ−８、ｎ＝０）置換体が得られる。Ｃ−４と３−イソシアナトプロパン酸エチル（CASRN 5100-34-5）又は４−イソシアナト酢酸エチル（CASRN 2949-22-6）との縮合（工程４）、その後の、分子内アシル化（工程７）により、それぞれ、２，５−ジオキソ−イミダゾリジン−１−イル（Ｃ−６、ｎ＝０）部分又は２，６−ジオキソ−テトラヒドロ−ピリミジン−１−イル（Ｃ−６、ｎ＝１）部分が得られる。２，４−ジオキソ−３，４−ジヒドロ−２Ｈ−ピリミジン−１−イル（Ｃ−９）部分は、臭素とウラシルとのＣｕＩ触媒置換により導入することができる（工程８）（R. Wagner等、国際公開公報第2009/039127号）。

Compounds of general formula I (wherein R ¹ is a heterocycle linked by a carbon-nitrogen bond) can be prepared by a copper or palladium catalyzed aryl amination reaction. Aryl amination methods have been described previously. The introduction of 2-oxo-tetrahydro-pyrimidin-1-yl or 2-oxo-imidazolidin-1-yl substituent can be achieved by bromoquinoline and 1,3-diamino-propane (step 1) or 1,2-diamino-ethane. (D. Ma et al., Org. Lett. 2003 5 (14): 2453) with CuI-catalyzed arylamination followed by intramolecular cyclization with carbonyldiimidazole (step 2). it can. Alternatively, a heterocyclic ring can be synthesized from the primary amine C-4. Numerous methods have been previously described for introducing primary amines into aryl rings by halogen substitution (Step 3) (JP Wolfe et al. Tetrahedron Lett. 1997 38 (36): 6367; C.-Z. Tao et al., Tetrahedron Lett. 2008 49:70; Q. Shen and JF Hartwig, J. Am. Chem. Soc. 2006 128: 10028; SS Surry and SL Buchwald, J. Am. Chem. Soc. 2007 129: 10354). By acylation of C-4 with 5-bromo-pentanoic acid (step 5) or 4-bromo-butyric acid followed by intramolecular cyclization (step 6), piperidone (C-8, n = 1, respectively). ) And pyrrolidone (C-8, n = 0) substitutions are obtained. Condensation of C-4 with ethyl 3-isocyanatopropanoate (CASRN 5100-34-5) or ethyl 4-isocyanatoacetate (CASRN 2949-22-6) (step 4), followed by intramolecular acylation (step 7), respectively, the 2,5-dioxo-imidazolidin-1-yl (C-6, n = 0) moiety or 2,6-dioxo-tetrahydro-pyrimidin-1-yl (C-6, n = 1) ) Part is obtained. The 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl (C-9) moiety can be introduced by CuI catalytic substitution of bromine and uracil (step 8) (R. Wagner et al. , International Publication No. 2009/039127).

Compounds of general formula A-5 (wherein the aryl-R ³ bond is a carbon-nitrogen bond) are optionally substituted with the bromo substituent of A-3 as illustrated in Examples 11 and 12. (JF Hartwig et al., J. Org. Chem. 1999 64: 5575).

  Substitution at the 2-position is via quinolone (Example 1), which is prepared by palladium-catalyzed cross-coupling of methyl acrylate with 20a and acid-catalyzed cyclization of lactam using the Heck protocol. O-alkylation of lactams gives 2-methoxy substituents. Reaction of quinolones with phosphorus oxyhalides gives 2-halo-quinolines, which can introduce other functionalities by substitution.

Introduction of an acyclic substituent at R ³ was accomplished by coupling a heteroaryl halide and an appropriately substituted alkene or alkyne using Heck coupling (see, eg, Example 29). The Heck reaction (or Mizoroki-Heck reaction) is a palladium catalyst of an aryl, alkenyl, alkynyl or benzyl halide or triflate with an alkene, styrene, acrylate ester, acrylonitrile enol ether or enol thioether containing at least one proton. Coupling (A. se Meijere and FE Meyer, Angew Chem. Int. Ed. English 1994 33: 2379-2411; W. Cabri and I. Candiani, Acc. Chem. Res. 1995 28 (1): 2- 7) Electron-deficient materials such as acrylic acid esters or MeCN are often used. Commonly used palladium catalysts include Pd (PPh ₃ ) ₄ , Pd (OAc) ₂ , PdCl ₂ , Pd ₂ (dba) ₃ . In general, phosphine ligands such as PPh ₃ , P (o-Tol) ₃ and BINAP are incorporated into the reaction mixture either as phosphine complexes or as free phosphines that can form complexes in situ. It is done. Typically, TEA, 1,2,2,6,6-pentamethyl - _{piperidine, DBU, K 2 CO 3,} KOAc, it is necessary to base such _Ag 2 CO ₃ and KO-tert-Bu. The reaction is generally carried out in an aprotic solvent, many in DMF, DMSO, NMP or MeCN; however, low polarity solvents and aqueous co-solvents may be used. Although some reactions can be varied, protocols have been established and those skilled in the art can identify useful conditions without undue experimentation.

Similar transformations give compounds of general formula I in which R ⁴ is other than tertiary butyl. Dibromination of 4- (1-methylcyclopropyl) benzeneamide (CASRN 114833-72-6) or 1- (4-aminophenyl) cyclopropanecarbonitrile (CASRN108858-86-2) results in a completely similar reaction sequence. An intermediate that can be provided is obtained. Alternatively, methyl 4-amino-5-bromo-2-methoxybenzoate (CASRN 111049-68-4) is obtained as methyl 3,8-dibromo-5-methoxy-quinoline-6-carboxylate (122a). It can be subjected to Skraup synthesis, which is converted to the corresponding cyclopropanecarbonitrile (124a) by conventional methods (see, eg, Example 25). Nitrile groups can be easily converted to the corresponding aldehydes (and therefore also the corresponding acids and esters) and from there to difluoromethyl (DAST fluorinated) or hydroxymethyl (BH ₃ reduced) substituents. Can be converted. Similar transformations can be used to obtain the corresponding demethoxy analog. 4-Trifluoromethyl-aniline (CASRN 455-14-1) and 3-methoxy-4-trifluoromethyl-aniline can be converted to quinoline and quinazoline analogs.

本発明に包含されるキナゾリンは、適切に置換されたオルト−ジアミノベンゼンと１，２−ジカルボニル化合物との縮合により調製された。例えば、グリオキシル酸エチルと３２を縮合して、５−ブロモ−７−tert−ブチル−１Ｈ−キノキサリン−２−オンと８−ブロモ−６−tert−ブチル−１Ｈ−キノキサリン−２−オンの混合物が得られた。Ｃ−３及びＣ−８置換基の導入は、上述したような連続置換により行うことができる（例えば、実施例２参照）。

The quinazolines encompassed by the present invention were prepared by condensation of an appropriately substituted ortho-diaminobenzene with a 1,2-dicarbonyl compound. For example, condensing ethyl glyoxylate with 32 to give a mixture of 5-bromo-7-tert-butyl-1H-quinoxalin-2-one and 8-bromo-6-tert-butyl-1H-quinoxalin-2-one Obtained. Introduction of C-3 and C-8 substituents can be performed by continuous substitution as described above (see, eg, Example 2).

一般式Ｉの化合物（式中、Ｘ^３は、Ｎであり、そして、Ｘ^１、Ｘ^２及びＸ^４は、ＣＲ^６である）は、Ｅ−３から、連続パラジウム触媒カップリングにより、上述したものと同様の条件を用いて、Ｒ^１及びＲ^３置換基を導入して調製される。Ｅ−１からＥ−２への変換は、Heckパラジウムカップリングプロトコールを用いて行われた。アセチレン酸のパラジウム触媒分子内ラクタム化により、６−エンド−ｄｉｇと５−エキソ−ｄｉｇ生成物の混合物である１５２ａ及び１５２ｂが生成した（H. Sashida and A. Kawamuki, Synthesis 1999 1145）。１５２ａをアンモニアに曝すと、対応するイソキノロンが得られ、これを、ＰＯＣｌ_３を用いてＥ−３に変換した。Ｅ−１の調製は、G.C. Colossi等の国際公開公報第2008/087057号に記載されている。

Compounds of general formula I, wherein X ³ is N and X ¹ , X ² and X ⁴ are CR ⁶ are described above from E-3 by continuous palladium catalyzed coupling. Prepared by introducing R ¹ and R ³ substituents using conditions similar to those described above. The conversion from E-1 to E-2 was performed using the Heck palladium coupling protocol. Palladium-catalyzed intramolecular lactamization of acetylenic acid produced 152a and 152b, a mixture of 6-endo-dig and 5-exo-dig products (H. Sashida and A. Kawamuki, Synthesis 1999 1145). Exposure of 152a to ammonia gave the corresponding isoquinolone, which was converted to E-3 using POCl ₃ . The preparation of E-1 is described in International Publication No. 2008/087057 such as GC Colossi et al.

一般式Ｉの化合物（式中、Ｘ^３及びＸ^２は、ＣＲ^６であり、そして、Ｘ^１及びＸ^４は、Ｎ（シンノリン誘導体）は、Ｆ−１から、連続パラジウム触媒カップリングにより、上述したものと同様の条件を用いて、Ｒ^１及びＲ^３置換基を導入して同様に調製される。Ｆ−２からＦ−１への変換は、オキシ臭化リンを用いて行われる。Ｆ−２は、Ｆ−３ｂを、ジエトキシアセチルクロリドで処理して、ヒドラジンにアシル化し、そして、分子内Friedel-Craftsアシル化を行い調製される。一般式Ｉの化合物（式中、Ｘ^１、Ｘ^２及びＸ^３は、ＣＲ^６である）は、Ｆ−５から調製さるＦ−４から同様に調製される。Ｆ−５は、Ｆ−６ａを同様に分子内Friedel-Craftsアシル化することで調製される。曖昧さを避けるために、スキームＥの矢印（「⇒」）は、逆合成の結合切断を示すことを理解されたい（E.J. Corey Angew. Chem. Intl. Ed. Engl. 1991 30:455）。

Compounds of general formula I, wherein X ³ and X ² are CR ⁶ and X ¹ and X ⁴ are N (cinnoline derivatives) from F-1 by continuous palladium catalyzed coupling as described above. Prepared similarly by introducing R ¹ and R ³ substituents using conditions similar to those described above The conversion of F-2 to F-1 is performed using phosphorus oxybromide. -2, the F-3b, treated with diethoxy chloride, acylated hydrazine, and is prepared make intramolecular Friedel-Crafts acylation. the compounds of general formula I (wherein, X ^1, X ² and X ³ are CR ⁶ ) are similarly prepared from F-4 prepared from F-5, F-5 is similarly intramolecular Friedel-Crafts acylating F-6a To avoid ambiguity, the arrow in Scheme E ("⇒") is It should be understood that it shows reverse synthetic bond cleavage (EJ Corey Angew. Chem. Intl. Ed. Engl. 1991 30: 455).

一般式Ｉの化合物（式中、Ｘ^１、Ｘ^２、Ｘ^３及びＸ^４は、ＣＲ^５である）は、ジブロモナフタレンＧ−１から、連続パラジウム触媒カップリングにより、上述したものと同様の条件を用いて、Ｒ^１及びＲ^３置換基を導入して調製した。Ｇ−１の調製は、Ｒ^１及びＲ^３部分を導入する連続Suzukiカップリングと共に、実施例２２に記載される。

Compounds of general formula I (wherein X ¹ , X ² , X ³ and X ⁴ are CR ⁵ ) are prepared from dibromonaphthalene G-1 by continuous palladium catalyst coupling under the same conditions as described above. Was used to introduce R ¹ and R ³ substituents. The preparation of G-1 is described in Example 22 with a continuous Suzuki coupling introducing the R ¹ and R ³ moieties.

  The activity of the compounds of the present invention as inhibitors of HCV activity can be measured by any suitable method known to those skilled in the art, including in vivo and in vitro assays. For example, the HCV NS5B inhibitory activity of a compound of formula I was measured by Behrens et al., EMBO J. 1996 15: 12-22, Lohmann et al., Virology 1998 249: 108-118 and Ranjith-Kumar et al. , J. Virology 2001 75: 8615-8623. Unless otherwise noted, in such standard assays, compounds of the present invention showed NS5B inhibitory activity of HCV in vitro. The HCV polymerase assay conditions used with the compounds of the invention are described in Example 8. A cell-based replicon system for HCV has been developed in which nonstructural proteins stably replicate subgenomic viral RNA in Huh7 cells (V. Lohmann et al., Science 1999 285: 110 and KJ Blight et al., Science 2000 290: 1972). Cell based replicon assay conditions for use with the compounds of the present invention are described in Example 4. In the absence of purified functional HCV replicase composed of viral nonstructural proteins and host proteins, our understanding of Flaviviridae RNA synthesis is to study with active recombinant RNA-dependent RNA polymerase And the validation of these studies in the HCV replicon system. Inhibition of purified recombinant HCV polymerase by compounds in in vitro biochemical assays was verified using a replicon system in which the polymerase is present in a replicase complex with other viruses and cellular polypeptides associated with the appropriate stoichiometry. Can be Demonstration of cell-based inhibition of HCV replication is more predictive of in vivo function than demonstration of NS5B inhibitory activity of HCV in in vitro biochemical assays.

  The compounds of the present invention can be formulated in a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coatings, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are continuous (infusion) topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (may include penetration enhancers), buccal, nasal, inhalation and other suppository administrations. Effective when administered by route of administration. The preferred manner of administration is generally oral using a conventional daily dosage regimen that can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

  The compounds of the present invention and pharmaceutically useful salts thereof can be in the form of pharmaceutical compositions and unit dosage forms, together with one or more conventional excipients, carriers or diluents. Pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional formulations with or without additional active compounds or active ingredients, and unit dosage forms are used Any suitable effective amount of the active ingredient corresponding to the intended daily dosage range can be included. The pharmaceutical composition can be used orally, as a solid formulation such as a tablet or filled capsule, a semi-solid formulation, a powder formulation, a sustained release formulation, or a liquid formulation such as a solution, suspension, emulsion, elixir or filled capsule Or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injections for parenteral use. A typical preparation will contain from about 5% to about 95% (w / w) of active compound (s). The term “formulation” or “dosage form” is intended to include both solid and liquid formulations of the active compound and the skilled person will know that the active ingredient is the target organ or tissue and the desired dosage and It will be understood that it exists in various formulations depending on the pharmacokinetic parameters.

  As used herein, the term “excipient” refers to a compound that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, biologically and otherwise desirable, Contains excipients acceptable for veterinary and human pharmaceutical use. While the compounds of the invention can be administered alone, they generally will comprise one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice. It is administered as a mixture.

  “Pharmaceutically acceptable” means generally useful in preparing pharmaceutical compositions that are safe, non-toxic, biologically and otherwise desirable, Includes what is acceptable.

  A “pharmaceutically acceptable salt” form of the active ingredient can also impart to the active ingredient the desired pharmacokinetic properties that were not initially shown in the non-salt form, and its therapeutic activity in the body. Can have a further positive effect on the pharmacodynamics of the active ingredient. The phrase “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, Glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methane Sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4 -Methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropio Acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, acid addition salt formed with muconic acid, or (2) acidic proton of parent compound Is substituted with a metal ion such as an alkali metal ion, alkaline earth metal ion or aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine or N-methylglucamine Salt formed.

  Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier is also one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. Also good. In the case of powders, the carrier is generally a finely divided solid which is mixed with the finely divided active ingredient. In the case of tablets, the active ingredient is generally mixed in an appropriate proportion with a carrier having the necessary binding capacity and compressed to the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

  Liquid formulations are also suitable for oral administration, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid form preparations that are intended to be converted into liquid form preparations immediately prior to use. Emulsions can be prepared in solution, for example, in aqueous propylene glycol solutions, or may contain an emulsifier such as lecithin, sorbitan oleic acid monoester or gum arabic. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water together with viscous materials such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.

  The compounds of the invention can be formulated for parenteral administration (eg, injection, eg, bolus injection or continuous infusion), in ampules, prefilled syringes, small volume infusion unit dosage forms, or preservatives May be present in added multi-dose containers. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous solvent such as an aqueous polyethylene glycol solution. Examples of oily or non-aqueous carriers, diluents, solvents or solvents include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate), preservatives, wetting agents, You may contain formulation agents, such as an emulsifier or a suspension agent, a stabilizer, and / or a dispersing agent. Alternatively, the active ingredient may be in the form of a powder obtained from aseptic isolation of a sterile solid or lyophilization of the solution to make up with a suitable solvent (eg, sterile pyrogen-free water) prior to use.

  The compounds of the present invention can be formulated for topical administration to the epithelium as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be formulated with an aqueous or oily base, for example, with the addition of suitable thickeners and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active agent in fragrance bases (usually sucrose and gum arabic or tragacanth); active ingredients in inert bases such as gelatin and glycerin or sucrose and gum arabic An aromatic tablet; and a mouthwash containing the active ingredient in a suitable liquid carrier.

  The compounds of the present invention can be formulated for suppository administration. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into an appropriately sized mold and allowed to cool and solidify.

  The compounds of the present invention can be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays contain, in addition to the active ingredient, carriers known to be suitable in the art. The compounds of the present invention can be formulated for nasal administration. Solutions or suspensions are applied directly to the nasal cavity using conventional means, for example with a dropper, pipette or spray. The formulation is provided in single dose or multiple dose forms. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate and predetermined amount of solution or suspension. In the case of a spray, this can be achieved, for example, using a metering spray pump.

  The compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. Generally, the compound has a small particle size, for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by atomization. The active ingredient is provided in a compressed pack with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. The aerosol may contain a surfactant such as lecithin for convenience. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredient can be provided in the form of a dry powder, eg, a powder mixture of the compound with a suitable powder base such as lactose, starch, starch derivatives, eg, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be in unit dose form, for example a gelatin capsule or cartridge, or a blister pack in which the powder can be administered by inhaler.

  If desired, formulations can be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is required and when it is crucial that the patient follows the treatment plan. In transdermal delivery systems, the compound is often bound to a skin adhesive solid support. The subject compounds can also be combined with penetration enhancers, such as azone (1-dodecylaza-cycloheptan-2-one). The slow broadcast delivery system is inserted subcutaneously into the subcutaneous layer by surgical treatment or injection. Subcutaneous implants encapsulate the compound in a fat-soluble film, such as silicone rubber or a biodegradable polymer, such as polylactic acid.

  A suitable formulation containing pharmaceutical carriers, diluents and excipients together is described in Remington: The Science and Practice of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Yes. A skilled pharmaceutical scientist can modify the formulation within the scope of the teachings herein without destabilizing the compositions of the present invention or compromising their therapeutic activity for a particular route of administration. A number of formulations can be provided.

  Modifications for dissolving the present compound with water or other solvents can be easily achieved by, for example, performing small-scale modifications (salt formation, esterification, etc.) known in the art. It is also known in the prior art in the art to modify the route of administration and regimen of a particular compound to manage the pharmacokinetics of the compound of the invention so that the patient has the maximum beneficial effect. is there.

  As used herein, the term “therapeutically effective amount” means the amount necessary to reduce the symptoms of an individual disease. The dose will be adjusted to the individual requirements in each particular case. The dose depends on many factors, such as the severity of the disease being treated, the age and general health of the patient, the other medications used in treating the patient, the route and form of administration, and the preferences of the attending physician It can be changed within a wide range according to experience. For oral administration, a daily dose of about 0.01 to about 1000 mg / kg body weight / day is appropriate for monotherapy and / or combination therapy. The daily dose is preferably about 0.1 to about 500 mg / kg body weight / day, more preferably 0.1 to about 100 mg / kg body weight / day, most preferably 1.0 to about 10 mg / kg body weight / day. Day. Thus, for a 70 kg human, the administered dose ranges from about 7 mg to 0.7 g / day. The daily dose can be administered in a single dose or in divided doses (typically 1-5 doses / day). Generally, treatment begins with a dosage that is less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is obtained. One skilled in the art of treating the diseases described herein will be able to rely on individual knowledge, experience and disclosure of the present application without undue experimentation to therapeutically effective amounts of the compounds of the present invention for the subject disease and patient. Would be able to confirm.

  In an embodiment of the invention, the active compound or salt is administered in combination with other antiviral agents such as ribavirin, nucleoside HCV polymerase inhibitors, other HCV non-nucleoside polymerase inhibitors or HCV protease inhibitors. Can do. When the active compound, derivative or salt thereof is administered in combination with other antiviral agents, the activity can be increased over the parent compound. When the treatment is a combination therapy, the administration can be simultaneous or sequential with the administration of the nucleoside derivative. Thus, “simultaneous administration” as used herein includes administering agents at the same time or at different times. Administration of two or more agents at the same time can be accomplished by a single formulation comprising two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent. .

  As used herein, it should be understood that treatment extends not only to treating an existing condition but also to prevention. Furthermore, the term “treatment” of HCV infection as used herein also includes treatment or prevention of a disease or condition associated with or mediated by HCV infection or clinical symptoms thereof.

  As used herein, the term “therapeutically effective amount” means the amount necessary to reduce the symptoms of an individual disease. The dose will be adjusted to the individual requirements in each particular case. The dose depends on many factors, such as the severity of the disease being treated, the age and general health of the patient, the other medications used in treating the patient, the route and form of administration, and the preferences of the attending physician It can be changed within a wide range according to experience. For oral administration, a daily dose of about 0.01 to about 1000 mg / kg body weight / day is appropriate for monotherapy and / or combination therapy. The daily dose is preferably about 0.1 to about 500 mg / kg body weight / day, more preferably 0.1 to about 100 mg / kg body weight / day, most preferably 1.0 to about 10 mg / kg body weight / day. Day. Thus, for a 70 kg human, the administered dose ranges from about 7 mg to 0.7 g / day. The daily dose can be administered in a single dose or in divided doses (typically 1-5 doses / day). Generally, treatment begins with a dosage that is less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is obtained. One skilled in the art of treating the diseases described herein will be able to rely on individual knowledge, experience and disclosure of the present application without undue experimentation to therapeutically effective amounts of the compounds of the present invention for the subject disease and patient. Would be able to confirm.

  A therapeutically effective amount of a compound of the invention, and optionally one or more additional antiviral agents, is an amount effective to reduce viral load or achieve a sustained viral response to therapy. In addition to viral load, useful indicators of sustained response include, but are not limited to, liver fibrosis, elevated serum transaminase levels, and hepatic necrotic inflammatory activity. A typical example of an exemplary but non-limiting marker is serum alanine transaminase levels (ALT) as measured in standard clinical assays. In some embodiments of the invention, an effective treatment regime is one that reduces ALT levels to less than about 45 IU / mL in serum.

  Modifications for dissolving the present compound with water or other solvents can be easily achieved by, for example, performing small-scale modifications (salt formation, esterification, etc.) known in the art. It is also known in the prior art in the art to modify the route of administration and schedule of a particular compound to manage the pharmacokinetics of the compound of the invention so that the patient has the maximum beneficial effect. is there.

Examples The following examples illustrate the preparation and biological evaluation of compounds within the scope of the present invention. These examples and preparations below are provided to enable those skilled in the art to more clearly understand and to practice the present invention. It should be understood that these are not intended to limit the scope of the invention, but are merely illustrative and exemplary thereof.

工程１ − ２０ａ（１０．０ｇ）及びＭｅＣＮ（２００mL）の溶液に、トリ−（ｏ−トリル）ホスフィン（１．３３ｇ）、Ｐｄ（ＩＩ）（ＯＡｃ）_２（０．７３０ｇ）、ＴＥＡ（６．８mL）及びアクリル酸メチル（２．３５mL）を添加した。反応物を１００℃で一晩撹拌した。反応物を冷却し、真空で濃縮した。粗生成物を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサングラジエント（０％ ＥｔＯＡｃを０〜５分、２０％ ＥｔＯＡｃを５．５〜１５分、そして、４０％ ＥｔＯＡｃを１５．５〜３０分）で溶離させて精製し、３．０２ｇの２０ｂを得た。 Example 1
N- {4- [6-tert-butyl-2-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide ( I-1)

Step 1—To a solution of 20a (10.0 g) and MeCN (200 mL), tri- (o-tolyl) phosphine (1.33 g), Pd (II) (OAc) ₂ (0.730 g), TEA (6. 8 mL) and methyl acrylate (2.35 mL) were added. The reaction was stirred at 100 ° C. overnight. The reaction was cooled and concentrated in vacuo. The crude product is eluted by SiO ₂ chromatography with an EtOAc / hexane gradient (0% EtOAc 0-5 min, 20% EtOAc 5.5-15 min, and 40% EtOAc 15.5-30 min). And purified to give 3.02 g of 20b.

Step 2-To a solution of 20b (6.73 g) and THF (150 mL) was added 6 N HCl (150 mL) and the resulting solution was heated at 100 <0> C overnight. The solution was cooled and concentrated in vacuo. The reaction mixture was basified with solid NaHCO ₃ and extracted three times with EtOAc (3 × 150 mL). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with the gradient described in step 1. The combined fractions were concentrated and triturated with Et ₂ O to give 22a as an off-white solid.

Step 3 To a solution of 22a (0.500 g, 1.78 mmol) in DCM (10 mL) cooled to 0 ° C. (ice bath), Br ₂ (90 μL, 1.78 mmol) was slowly added via syringe. The reaction was stirred for 3 hours while warming to room temperature and then concentrated. The crude mixture was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (stepwise to 0, 20, 40% EtOAc) to give 0.273 g (42%) of 22b.

Step 4 - 22b (0.273g, 0.76mmol) in MeCN (10 mL) solution of _was added POCl 3 (0.14mL, 1.52mmol). The reaction was heated at 100 ° C. for 8 hours, then concentrated and partitioned between EtOAc and water (25 mL / 25 mL). The aqueous layer was separated and washed twice with EtOAc (2 × 25 mL). The combined extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give 0.287 g (100%) of 24a.

Step 5-To a solution of 24a (0.242 g, 0.64 mmol) and DMF (2 mL) was added sodium methoxide (1.54 mL, 0.5 M MeOH solution, 0.769 mmol). The reaction was heated at 90 ° C. for 30 min, then concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give 0.239 g (100%) of 24b.

Step 6—In a vial containing 24b (0.100 g, 0.26 mmol) and MeOH / DCM (3 mL / 1 mL), Na ₂ CO ₃ (0.082 g, 0.78 mmol), 4-methylsulfonylamino-phenylboron. Acid (25, 0.056 g, 0.26 mmol) and Pd (PPh ₃ ) ₄ (0.030 g, 0.26 mmol) were added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc / H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was EtOAc / hexanes gradient by SiO ₂ flush (stepwise from 0-5 minutes with 0% EtOAc, 5.5-15 minutes with 20% EtOAc, and 15.5-30 minutes with 40% EtOAc). To give 0.068 g (57%) of 26.

Step 7 - MeOH / DCM (3mL / 1mL) in dissolved was 26 (0.061g, 0.13mmol) in a solution _{of, Na 2 CO 3 (0.041g,} 0.40mmol), 30 (0.017g, 0 .16 mmol) and Pd (PPh ₃ ) ₄ (0.015 g, 0.013 mmol) were added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by preparative development on a preparative SiO ₂ TLC plate with 40% EtOAc / hexanes, then dried and re-eluted with 100% EtOAc to yield 0.013 g (21%) of I-1. Obtained.

工程１ − ４−tert−ブチル−２−ニトロアニリン（３１ａ、５．０ｇ、２５．７４mmol）に、ＨＯＡｃ（４０mL）を添加した。清澄な橙褐色の溶液が生じるまで、反応物を５０℃で加熱した。マントルヒータを取り除き、臭素（１．４６mL、２８．３２mmol）をシリンジで慎重に添加した。反応物を、室温に冷ましながら４５分間以上撹拌した後、氷（１００mL）に注いだ。スラリーをガラス棒で撹拌したところ、氷が溶けるにつれ固体がさらに沈殿した。固体をガラスフリット上に集め、乾燥させて、６．９５ｇ（９９％）の３１ｂを得た。 Example 2
N- {4- [7-tert-butyl-5- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide ( I-2)

Step 1-To 4-tert-butyl-2-nitroaniline (31a, 5.0 g, 25.74 mmol) was added HOAc (40 mL). The reaction was heated at 50 ° C. until a clear orange-brown solution resulted. The mantle heater was removed and bromine (1.46 mL, 28.32 mmol) was carefully added with a syringe. The reaction was stirred for more than 45 minutes while cooling to room temperature and then poured onto ice (100 mL). The slurry was stirred with a glass rod, and more solid precipitated as the ice melted. The solid was collected on a glass frit and dried to give 6.95 g (99%) of 31b.

Step 2 - 31b (2.5g, 9.15mmol) in _{MeOH / H 2 O (100mL /} 25mL) solution of electrolytic iron (1.53g, 27.46mmol) and _NH 4 Cl (1.47g, 27.46mmol ) Was added. The reaction was heated to reflux for 4 hours and then filtered through glass fiber filter using a Buchner funnel to remove iron. The solid was rinsed with MeOH and the filtrate was concentrated and partitioned between EtOAc and H ₂ O (50 mL / 50 mL). The aqueous layer was separated and washed with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give 2.23 g (100%) of 32.

Step 3-32 To a solution of 32 (0.500 g, 1.8 mmol) in EtOH was added ethyl glyoxalate (50% (by weight) toluene solution, 0.54 mL, 2.7 mmol). The reaction was heated to reflux overnight. Additional ethyl glyoxalate (0.54 mL, 2.7 mmol) was added and the reaction was again heated to reflux overnight. The off-white precipitate was collected on a glass frit to give 0.280 g (51%) of 34 (other isomers were also present in the crude mixture but were not isolated).

Step 4 - MeCN 34 was suspended in (10mL) (0.269g, 0.96mmol) in _was added POCl 3 (0.52mL, 5.74mmol). The reaction was heated at 100 ° C. for 3 h, then concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give 0.286 g (quantitative) of 36a.

Step 5 - 36a (0.050g, 0.17mmol) in MeOH and DCM (3 mL / 1 mL) solution _{of, Na 2 CO 3 (0.053g,} 0.50mmol), 4- methylsulfonylamino - phenylboronic acid (0 0.028 g, 0.13 mmol) and Pd (PPh ₃ ) ₄ (0.019 g, 0.017 mmol) were added. The reaction was irradiated by microwave at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was graded by SiO ₂ chromatography to an EtOAc / hexane gradient (0-5 min with 0% EtOAc, 5.5-15 min with 20% EtOAc, and 15.5-30 min with 40% EtOAc). ) To give 0.042 g (58%) of 36b.

Step 6—To 36b (0.056 g, 0.13 mmol) dissolved in MeOH and DCM (3 mL / 1 mL) was added Na ₂ CO ₃ (0.041 g, 0.39 mmol), 5-fluoro-2-methoxy-3. -(4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridine (40, 0.026 g, 0.16 mmol, CASRN 1083168-95-9) and Pd (PPh ₃ ) ₄ (0.015 g, 0.013 mmol) was added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was graded by SiO ₂ chromatography to an EtOAc / hexane gradient (0-5 min with 0% EtOAc, 5.5-15 min with 20% EtOAc, and 15.5-30 min with 40% EtOAc). ) To give 0.061 g (100%) of 38.

Step 7-38 To a solution of 38 (0.058 g, 0.148 mmol) in HOAc (2 mL) was added HBr (0.1 mL, 50% aqueous solution). The reaction in a sealed tube was heated at 70 ° C. overnight in a sand bath. The reaction was cooled, poured onto ice (25 mL) and saturated aqueous NaHCO ₃ (25 mL) was added slowly. The ice was melted and the resulting precipitate was collected on a glass frit to give 0.034 g (61%) of I-2.

I-6 was prepared similarly except that 40 was replaced with 30 in step 6. The crude product was adsorbed onto SiO ₂ and purified by SiO ₂ chromatography eluting with 10% MeOH / DCM.

Example 3
N- {1- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -piperidin-4-yl} -methanesulfonamide ( I-3)
Step 1-DMF (2 mL) solution of 36a (0.100 g, 0.33 mol) and N-piperidin-4-ylmethanesulfonamide HCl salt (37, 0.143 g, 0.66 mmol, CASRN 70724-72-0) To was added DIPEA (0.2 mL, 1.00 mmol). The reaction was irradiated with a microwave synthesizer at 140 ° C. for 30 minutes. The reaction mixture was cooled, concentrated, adsorbed onto SiO ₂ and purified by SiO ₂ chromatography eluting with 5% MeOH / DCM to give 0.102 g (69%) N- [1- (5- Bromo-7-tert-butyl-quinoxalin-2-yl) -piperidin-4-yl] -methanesulfonamide (42) was obtained.

Step 2 - 42 (0.040g, 0.10mmol) in MeOH and DCM (3mL / 1mL) solution _{of, Na 2 CO 3 (0.029g,} 0.27mmol), 30 (0.012g, 0.11mmol) and Pd (PPh ₃ ) ₄ (0.010 g, 0.010 mmol) was added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc / H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was adsorbed onto SiO ₂ and purified by SiO ₂ chromatography eluting with 10% MeOH / DCM to give 0.030 g (73%) of 1-3.

I-5 was prepared in the same manner except that in Step 2, 30 was replaced with 40 and demethylation was performed as described in Step 7 of Example 2. The crude product was purified by SiO ₂ chromatography eluting with 10% MeOH / DCM.

Example 4
N-{(S) -1- [7-tert-butyl-5- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -pyrrolidine-3 -Ilmethyl} -methanesulfonamide (I-4)
Step 1-36a (0.050 g, 0.13 mmol) and N- (S) -1-pyrrolidin-3-ylmethyl-methanesulfonamide HCl salt (44, 0.053 g, 0.25 mmol, CASRN 1064048-61-8 ) In DMF (2 mL) was added DIPEA (0.1 mL, 0.50 mmol). The reaction was irradiated with a microwave synthesizer at 140 ° C. for 30 minutes. The reaction mixture was cooled, concentrated, adsorbed on silica and purified by SiO ₂ chromatography eluting with 5% MeOH / DCM to give 0.050 g (68%) N-[(S) -1- (5-Bromo-7-tert-butyl-quinoxalin-2-yl) -pyrrolidin-3-ylmethyl] methanesulfonamide (46) was obtained.

Steps 2-46 and 40 Suzuki cross couplings were performed as described in Step 6 of Example 2. The crude product was purified by SiO ₂ chromatography eluting with 5% MeOH / DCM (500 mL) followed by 10% MeOH / DCM (500 mL) to give 0.047 g (89%) N-{(S) -1- [7-tert-butyl-5- (5-fluoro-2-methoxy-pyridin-3-yl) -quinoxalin-2-yl] -pyrrolidin-3-ylmethyl} -methanesulfonamide (48) is obtained. It was.

Steps 3-48 were demethylated as described in Step 7 of Example 2. The crude product was purified by preparative SiO ₂ TLC plate by sequential development with 100% EtOAc, then 5% MeOH / DCM to afford 1-4.

工程１ − ＭｅＯＨ及びＤＣＭ（９mL／３mL）に溶解させた３６ａ（０．２１６ｇ、０．７２mmol）に、Ｎａ_２ＣＯ_３（０．２２９ｇ、２．２mmol）、５２（０．１４６ｇ、０．５８mmol、CASRN 877160-63-9）及びＰｄ（ＰＰｈ_３）_４（０．０８３ｇ、０．０７２mmol）を添加した。反応物を、マイクロ波シンセサイザーにより１１５℃で３０分間照射した。反応物を冷却して、濃縮し、ＥｔＯＡｃ及びＨ_２Ｏ（２５mL／２５mL）で分液した。水層を分離し、ＥｔＯＡｃ（２×２５mL）で洗浄した。合わせた有機抽出物を、食塩水（２５mL）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。粗生成物を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサングラジエント（０、２０、４０％ ＥｔＯＡｃに段階的）で溶離させて精製し、０．１４２ｇ（５１％）の５０ａを得た。 Example 5
N- {4- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide (I-6)

Step 1 - MeOH and DCM (9mL / 3mL) in The dissolved 36a (0.216g, 0.72mmol) _{in, Na 2 CO 3 (0.229g,} 2.2mmol), 52 (0.146g, 0.58mmol CASRN 877160-63-9) and Pd (PPh ₃ ) ₄ (0.083 g, 0.072 mmol) were added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (stepwise to 0, 20, 40% EtOAc) to give 0.142 g (51%) of 50a.

Step 2 To a solution of 50a (0.140 g, 0.36 mmol) and DCM was added pyridine (21 μL, 0.39 mmol) and the solution was cooled to 0 ° C. (ice bath). Methanesulfonyl chloride (46 μL, 0.39 mmol) was added and after 15 minutes the ice bath was removed and the reaction was warmed to room temperature and stirred for 3 hours. The reaction was concentrated and partitioned between EtOAc (25 mL) and saturated aqueous NaHCO ₃ (25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (stepwise to 0, 20, 40% EtOAc) to give 0.110 g (66%) of 50b.

Step 3 - the vial, 50b (0.110g, 0.24mmol), was placed in MeOH and DCM (3mL / 1mL), _{then, Na 2 CO 3 (0.075g,} 0.71mmol), 30 (0.030g 0.28 mmol) and Pd (PPh ₃ ) ₄ (0.027 g, 0.024 mmol) were added. The reaction was irradiated with a microwave synthesizer at 115 ° C. for 30 minutes. The reaction was cooled, concentrated and partitioned between EtOAc and H ₂ O (25 mL / 25 mL). The aqueous layer was separated and washed with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was adsorbed onto SiO ₂ and purified by SiO ₂ chromatography eluting with 5% MeOH / DCM to afford 0.043 g (38%) of I-6.

  I-8 was prepared in the same manner except that in step 1, 52 was replaced with 4-amino-2-fluorophenylboronic acid pinacol ester (CASRN 819057-45-9).

  I-9 was prepared in the same manner except that in step 3, 30 was replaced with 2,6-dimethoxypyridine-3-boronic acid and the methyl ether was cleaved according to the procedure of step 7 of Example 1.

  I-11 is exchanged in step 1, 52 to 4-amino-2-fluorophenylboronic acid pinacol ester, in step 3, 30 is exchanged to 2,6-dimethoxypyridine-3-boronic acid, and Methyl ether was prepared in the same manner except that it was cleaved according to the procedure of Step 7 of Example 2.

工程１ − ３２（２．５ｇ、１０．２８mmol）及びＥｔＯＨ（４０mL）の溶液に、ピルビン酸（０．８６mL、１２．３４mmol）を添加した。反応物を１００℃（還流下）で加熱し、２時間撹拌した。溶液を、一晩かけてゆっくり室温に冷ますると沈殿が生じた。結晶をガラスフリット上に集めたが、両方の異性体を含有していたため、母液を合わせ濃縮した。粗生成物を、ＳｉＯ_２クロマトグラフィーにより２０％ ＥｔＯＡｃ／ヘキサンで溶離させて精製し、０．６９４ｇの５４（２３％）及び０．９３１ｇの５６（３１％）を得た。 Example 6
N- {4- [7-tert-butyl-3-methyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide ( I-10)

Step 1-32 To a solution of 32 (2.5 g, 10.28 mmol) and EtOH (40 mL) was added pyruvic acid (0.86 mL, 12.34 mmol). The reaction was heated at 100 ° C. (under reflux) and stirred for 2 hours. The solution was allowed to cool slowly to room temperature overnight and a precipitate formed. The crystals were collected on a glass frit and contained both isomers, so the mother liquors were combined and concentrated. The crude product was purified by SiO ₂ chromatography eluting with 20% EtOAc / hexanes to give 0.694 g of 54 (23%) and 0.931 g of 56 (31%).

54 was converted to I-10 according to steps 4-6 of Example 2 except that step 6 was replaced with 30 and step 7 was omitted in step 6. The crude product was adsorbed onto SiO ₂ and purified by SiO ₂ chromatography eluting with 5% MeOH / DCM to afford I-10.

工程１ − マイクロ波バイアルに、５８（５８７mg、２．５７mmol）、５−フルオロ−２−メトキシ−ピリジン−３−イルボロン酸（５９、６６０mg、３．８６mmol）、Ｐｄ（ＰＰｈ_３）_４（１４８mg、０．１２mmol）、Ｎａ_２ＣＯ_３（８１８mg、７．８mmol）及びＭｅＯＨ（０．７mL）／ＤＣＭ（３．５mL）を入れ、密封し、マイクロ波シンセサイザーにより１１５℃で２時間照射した。反応混合物を室温に冷まし、ＥｔＯＡｃで希釈した。有機層を水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗残渣を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサングラジエントで溶離させて精製し、４６０mg（６５％）の６０を褐色の油状物として得た。 Example 7
N- {4- [7-tert-butyl-5- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-chloro-phenyl}- Methanesulfonamide (I-12)

Step 1—In a microwave vial, 58 (587 mg, 2.57 mmol), 5-fluoro-2-methoxy-pyridin-3-ylboronic acid (59, 660 mg, 3.86 mmol), Pd (PPh ₃ ) ₄ (148 mg, 0.12 mmol), Na ₂ CO ₃ (818 mg, 7.8 mmol) and MeOH (0.7 mL) / DCM (3.5 mL), sealed, and irradiated by a microwave synthesizer at 115 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient to give 460 mg (65%) of 60 as a brown oil.

Step _{2 - Br 2 (191mg, 1.6mmol} ) colors HOAc (5 mL) solution of reddish room temperature, alpha-bromo-acrolein (230 mg, 1.71 mmol) in HOAc (5 mL) was added excess bromine faint Until it appears. After stirring for 15 minutes at room temperature, a solution of 60 (437 mg, 1.59 mmol) in HOAc (5 mL) was added. The reaction mixture was heated at 100 ° C. for 2 hours. The reaction mixture was carefully poured into chilled saturated aqueous NaHCO ₃ and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 1: 1 hexane / ethyl acetate to give 260 mg (43%) of 62 as a brown oil.

Step 3—In a microwave vial, 62 (60 mg, 0.16 mmol), 25 (52 mg, 0.241 mmol), Pd (PPh ₃ ) ₄ (10 mg, 0.008 mmol) and Na ₂ CO ₃ (51 mg, 0.48 mmol). ) In MeOH (0.1 mL) and DCM (0.5 mL), sealed and irradiated by a microwave synthesizer at 115 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with EtOAc to give 32 mg (42%) of I-12 as an off-white solid: MS (ES) (M + H) ⁺ = 466

Example 8
N- {1- [6-tert-butyl-8- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -piperidin-4-yl}- Methanesulfonamide (I-13)
In a vial, 62 (70 mg, 0.187 mmol), 37 (44 mg, 0.205 mmol), Pd (OAc) ₂ (4 mg, 0.018 mmol), NaO-tert-Bu (72 mg, 0.75 mmol) and P (tert -Bu) ₃ (4 mg, 0.018 mmol) in toluene (3 mL) was charged, sealed and heated at 100 <0> C for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by preparative SiO ₂ TLC plate developed with 9: 1 DCM / MeOH to give 28 mg (32%) of I-13 as a brown oil: MS (ES) (M + H) ⁺ = 473

工程１ − ６４ａ（６ｇ、２８．８４mmol、CASRN 79822-46-1）、ジフェニルホスホリルアジド（８ｇ、２９．０９mmol）、ＴＥＡ（４．３２mL、３０．９９mmol）のtert−ブタノール（５００mL）混合物を、一晩加熱還流した。反応混合物を室温に冷まし、揮発性物質を蒸発させた。粗物質を、０℃で、ＴＦＡ及びＤＣＭ（２０mL）の１：１混合物で処理した。室温で３時間撹拌した後、反応混合物を０℃に冷却し、２ＭのＮａＯＨ水溶液で処理した。反応混合物をヘキサンで希釈して、分離し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗残渣を、ＳｉＯ_２クロマトグラフィーにより１：４のＥｔＯＡｃ／ヘキサンで溶離させて精製し、３．４ｇ（６６％）の６４ｂを褐色の油状物として得た。 Example 9
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide ( I-14)

Step 1-A mixture of tert-butanol (500 mL) of 64a (6 g, 28.84 mmol, CASRN 79822-46-1), diphenylphosphoryl azide (8 g, 29.09 mmol), TEA (4.32 mL, 30.99 mmol) Heated to reflux overnight. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The crude material was treated with a 1: 1 mixture of TFA and DCM (20 mL) at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 0 ° C. and treated with 2M aqueous NaOH. The reaction mixture was diluted with hexanes, separated, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 1: 4 EtOAc / hexanes to give 3.4 g (66%) of 64b as a brown oil.

Step 2-NBS (498 mg, 2.7 mmol) was added to a solution of 64b (500 mg, 2.7 mmol) in MeCN (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed with 1N NaOH, dried (MgSO ₄ ), filtered and concentrated to give 700 mg of 66 as a brown oil.

Step 3 - a microwave vial, 66 (700mg, 2.71mmol), 30 (612mg, 4mmol), Pd (PPh 3) 4 (231mg, 0.2mmol) and _{Na 2 CO 3 (636mg, 6mmol} ), MeOH ( 1 mL) and DCM (9 mL), sealed, and irradiated with a microwave synthesizer at 115 ° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient to give 420 mg (54%) of 68 as a brown oil.

Step _{4 - Br 2 (191mg, 1.6mmol} ) and HOAc (5 mL) solution of at room temperature, alpha-bromo-acrolein (230 mg, 1.71 mmol) in HOAc (5 mL) was added a faint reddish color bromine Added until present. After stirring for 15 minutes at room temperature, a solution of 68 (420 mg, 1.47 mmol) in HOAc (5 mL) was added. The reaction mixture was heated at 100 ° C. for 2 hours. The reaction mixture was carefully poured into chilled saturated aqueous NaHCO ₃ and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 1: 1 hexane / EtOAc to give 150 mg (26%) of 70 as a brown oil: MS (ES) (M + H) ⁺ = 388.

Step 5—In a microwave vial, 70 (150 mg, 0.387 mmol), 25 (125 mg, 0.581 mmol), Pd (PPh ₃ ) ₄ (45 mg, 0.038 mmol), Na ₂ CO ₃ (123 mg, 1.16 mmol) ), MeOH (0.2 mL) and DCM (1.5 mL), sealed, and irradiated by a microwave synthesizer at 115 ° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 95: 5 DCM / MeOH to give 40 mg (21%) of I-14 as an off-white solid.

Example 10
N- {4- [6-tert-butyl-8- (5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide (I-15)
NCS (15 mg, 0.112 mmol) was added to a solution of 1-14 (48 mg, 0.1 mmol) in MeCN (5 mL) and DMF (2 mL) warmed to 70 ° C. The reaction mixture was stirred at 70 ° C. for 5 hours, then cooled to room temperature and diluted with EtOAc. The organic layer was washed with H ₂ O, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient to give 25 mg (49%) of I-15 as a white solid.

Example 11
N- {1- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -azetidin-3-ylmethyl}- Methanesulfonamide (I-19) and N- {1- [6-tert-butyl-4-chloro-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoline -3-yl] -azetidin-3-ylmethyl} -methanesulfonamide (I-22)
Step 1—Into a vial, 70 (301 mg, 0.77 mmol), N-azetidin-3-ylmethyl-methanesulfonamide hydrochloride (200 mg, 0.934 mmol), Pd (OAc) ₂ (18 mg, 0.08 mmol), NaO A solution of tert-Bu (298 mg, 3.1 mmol) and P (tert-Bu) ₃ (16 mg, 0.079 mmol) in toluene (3 mL) was added, sealed and heated at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with a DCM / MeOH gradient to give 95 mg (26%) of I-19 as an off-white solid.

Step 2-NCS (14 mg, 0.105 mmol) was added to a solution of I-19 (45 mg, 0.095 mmol) in MeCN (5 mL) at 70 <0> C. The reaction mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 1N NaOH, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by preparative SiO ₂ TLC plate developed with 9: 1 DCM / MeOH to give 13 mg (27%) of I-22 as a semi-solid.

Example 12
N-{(S) -1- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -pyrrolidine-3 -Ilmethyl} -methanesulfonamide (I-18)
N-pyrrolidin-3-ylmethyl-methanesulfonamide (72) -TEA (1.05 mL, 7.5 mmol) was added at 0 ° C. to (R) -3- (aminomethyl) -1-N-Boc-pyrrolidine ( 1 g, 5 mmol) in DCM (25 mL) was added. Then methanesulfonyl chloride (0.43 mL, 5.5 mmol) was added. After stirring at 0 ° C. for 2 hours, the reaction mixture was diluted with water. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated. The crude material was treated with 1M HCl in MeOH (25 mL) at room temperature and stirred at room temperature for 20 hours. Volatiles were removed under reduced pressure to give 0.95 g of 72 as a white solid.

Step 1-In a vial, 70 (301 mg, 0.77 mmol), 72 (200 mg, 0.778 mmol), Pd (OAc) ₂ (18 mg, 0.08 mmol), NaO-tert-Bu (298 mg, 3.1 mmol) and A solution of P (tert-Bu) ₃ (16 mg, 0.079 mmol) in toluene (3 mL) was added, sealed and heated at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 9: 1 DCM / MeOH to give 60 mg (16%) I-18 and 60 mg (25%) 3- (6-tert-butyl-5- Methoxy-quinolin-8-yl) -1H-pyridin-2-one [(M + H) ⁺ = 309] was obtained as a white solid.

工程１ − Ｂｒ_２（１２６mg、１．０５mmol）のＨＯＡｃ（５mL）溶液を、室温で、α−ブロモアクロレイン（１４８mg、１．１mmol）のＨＯＡｃ（５mL）溶液に、臭素のかすかな赤みがかった色が存在するまで添加した。室温で１５分間撹拌した後、６６（２６０mg、１．０１mmol）のＨＯＡｃ（５mL）溶液を添加した。反応混合物を、１００℃で４時間加熱した。反応混合物を、冷やした飽和ＮａＨＣＯ_３水溶液に慎重に注ぎ、次に、ＥｔＯＡｃで抽出した。有機層を食塩水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗残渣を、ＳｉＯ_２クロマトグラフィーによりヘキサン／ＥｔＯＡｃグラジエントで溶離させて精製し、１７０mg（４５％）の７４ａを褐色の油状物として得た。 Example 13
N- {4- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide (I-21)

Step _{1 - Br 2 (126mg, 1.05mmol} ) and HOAc (5 mL) solution of at room temperature, alpha-bromo-acrolein (148 mg, 1.1 mmol) in HOAc (5 mL) was added a faint reddish color bromine Added until present. After stirring for 15 minutes at room temperature, a solution of 66 (260 mg, 1.01 mmol) in HOAc (5 mL) was added. The reaction mixture was heated at 100 ° C. for 4 hours. The reaction mixture was carefully poured into chilled saturated aqueous NaHCO ₃ and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with a hexane / EtOAc gradient to give 170 mg (45%) of 74a as a brown oil.

Step 2 - the vials, 74a (850mg, 2.27mmol), 25 (539mg, 2.5mmol), Pd (PPh 3) 4 (263mg, 0.227mmol), Na 2 CO 3 (725mg, 6.83mmol), MeOH (8 mL) and DCM (5 mL) were charged, sealed, and irradiated with a microwave synthesizer at 120 ° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with EtOAc to give 600 mg (57%) of 74b as an off-white solid: MS (ES) (M + H) ⁺ = 464.

Step 3-In a vial, 74b (200 mg, 0.431 mmol), uracil (72 mg, 0.642 mmol), N- (2-cyanophenyl) picolinamide (19 mg, 0.085 mmol), CuI (8 mg, 0.042 mmol) , K ₃ PO ₄ (183 mg, 0.86 mmol), DCM and MeOH were added before degassing. DMSO (1.5 mL) was added. The vial was sealed and irradiated with a microwave synthesizer at 150 ° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 1N NaHSO ₄ , dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with EtOAc to give 17 mg (8%) of I-21 as a semi-solid.

  N-{(S) -1- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -Pyrrolidin-3-ylmethyl} -methanesulfonamide (I-55) was prepared from 74a using Suzuki coupling with 115 and demethylation according to the procedure of steps 2 and 3 of Example 24. The

５mLのマイクロ波バイアルに、７４ｂ（９８．７mg、０．２１３mmol）、２，４−ジオキソ−１，２，３，４−テトラヒドロ−ピリミジン−５−イルボロン酸（６７．９mg、０．４３６mmol、CASRN 70523-22-7）、Ｎａ_２ＣＯ_３（１１９．８mg、１．１３mmol）及びＰｄ（ＰＰｈ_３）_４（２７．８mg、０．０２４mmol）、ＭｅＯＨ（１．６mL）及びＤＣＭ（０．４mL）を入れ、密封し、マイクロ波シンセサイザーにより１１５℃で６０分間照射した。室温に冷ました後、反応混合物を飽和ＮａＨＣＯ_３水溶液（３０mL）に注ぎ、ＥｔＯＡｃ（３×２０mL）で抽出した。合わせた抽出物を、飽和ＮａＨＣＯ_３水溶液（２×４０mL）、食塩水（４０mL）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。粗生成物を、ＳｉＯ_２クロマトグラフィーによりＭｅＯＨ／ＤＣＭグラジエント（２〜１０％ ＭｅＯＨ）で溶離させて精製し、１５mg（１４％）のＩ−２５を明黄色の固体として得た。 Example 14
N- {4- [6-tert-butyl-8- (2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -5-methoxy-quinolin-3-yl] -phenyl } -Methanesulfonamide (I-25)

In a 5 mL microwave vial, 74b (98.7 mg, 0.213 mmol), 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid (67.9 mg, 0.436 mmol, CASRN 70523-22-7), Na ₂ CO ₃ (119.8 mg, 1.13 mmol) and Pd (PPh ₃ ) ₄ (27.8 mg, 0.024 mmol), MeOH (1.6 mL) and DCM (0.4 mL) Was sealed, and irradiated with microwave synthesizer at 115 ° C. for 60 minutes. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO ₃ (30 mL) and extracted with EtOAc (3 × 20 mL). The combined extracts were washed with saturated aqueous NaHCO ₃ (2 × 40 mL), brine (40 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by eluting with MeOH / DCM gradient (2 to 10% MeOH) by SiO ₂ chromatography to afford I-25 in 15 mg (14%) as a light yellow solid.

I-23 was replaced according to the procedure of Example 7, step 7 with the exchange of 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid to 59 and cleaving the methyl ether. Prepared in the same manner. The crude product was purified by SiO ₂ chromatography eluting with a MeOH / DCM gradient (2-5% MeOH) to give I-23 as an off-white solid.

  1-24 according to the procedure of Example 7, step 7, 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid to 2-methoxy-6-methyl-pyridine-3- It was prepared in the same manner except that it was replaced with ylboronic acid (CASRN 1000802-75-4) and the methyl ether was cleaved. The crude product precipitated out as yellow crystals.

I-26 was prepared similarly except that 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid was replaced with 3-fluoro-pyridin-4-ylboronic acid. The crude product precipitated out as yellow crystals. The crude product was purified by SiO ₂ chromatography eluting with a MeOH / DCM gradient (2-5% MeOH) to give I-26 as an off-white solid.

  I-34 was replaced according to the procedure of Example 7, step 7 with the exchange of 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid to 115 and cleaving the methyl ether. Prepared in the same manner.

バイアルに、７４ｂ（８０mg、０．１７２mmol）、１，３−プロパンジアミン（３００μL）、Ｄ，Ｌ−プロリン（８mg、０．０６９mmol）、ＣｕＩ（８mg、０．０３６mmol）、Ｋ_２ＣＯ_３（９６mg、０．６９５mmol）を入れ、脱気して、ＤＭＳＯ（０．５mL）を添加した。反応混合物を、１５０℃で４８時間加熱した。反応混合物を室温に冷まし、ＥｔＯＡｃで希釈した。有機層を水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗残渣をＴＨＦ（５mL）に溶解させ、カルボニルジイミダゾール（３５０mg）で処理した。室温で４時間撹拌した後、反応物をＥｔＯＡｃで希釈した。有機層を水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。アミンは、完全に環化していなかった。従って、その物質をジオキサン（１５mL）に溶解させ、マイクロ波反応器により１５０℃で３０分間照射した。反応混合物を室温に冷まし、濃縮した。粗残渣を、分取ＳｉＯ_２ＴＬＣプレートにより９５：５のＤＣＭ／ＭｅＯＨで展開させて精製し、１５mg（１８％）のＩ−２７を明黄色の固体として得た。 Example 15
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-tetrahydro-pyrimidin-1-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide (I-27)

In a vial, 74b (80 mg, 0.172 mmol), 1,3-propanediamine (300 μL), D, L-proline (8 mg, 0.069 mmol), CuI (8 mg, 0.036 mmol), K ₂ CO ₃ (96 mg). , 0.695 mmol), degassed and DMSO (0.5 mL) was added. The reaction mixture was heated at 150 ° C. for 48 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was dissolved in THF (5 mL) and treated with carbonyldiimidazole (350 mg). After stirring at room temperature for 4 hours, the reaction was diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The amine was not completely cyclized. Therefore, the material was dissolved in dioxane (15 mL) and irradiated in a microwave reactor at 150 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and concentrated. The crude residue by preparative _SiO 2 TLC plate 95 was purified by developed with 5 of DCM / MeOH, to give the I-27 in 15 mg (18%) as a light yellow solid.

Ｂ−（２，３−ジヒドロ−３−オキソ−４−ピリダジニル）−ボロン酸（７８）：
工程ａ − １Ｌの丸底フラスコに、４−クロロ−５−ヒドラジニル−３（２Ｈ）−ピリダジノン（８．０ｇ、５０mmol、CASRN 6959-56-4）、ＣｕＳＯ_４・５Ｈ_２Ｏ（２６．１２ｇ、１０．５mmol）及びＨ_２Ｏ（３００mL）を入れ、混合物を撹拌して、一晩加熱還流した。反応物を０℃に冷却し、ｐＨが４になるまでＮａＯＨ水溶液を添加した。水層をＥｔＯＡｃ（各５００mL）で２回抽出した。合わせた抽出物を、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。残留水相を３７％ ＨＣｌでｐＨ２に調整し、溶液をＥｔＯＡｃで６回抽出した。抽出物を合わせ、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮し、４．７５ｇの４−クロロ−２Ｈ−ピリダジン−３−オン（７５）を得た。 Example 16
N- {4- [6-tert-butyl-5-methoxy-8- (3-oxo-2,3-dihydro-pyridazin-4-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide ( 76)

B- (2,3-dihydro-3-oxo-4-pyridazinyl) -boronic acid (78):
Step a-1 To a 1 L round bottom flask was added 4-chloro-5-hydrazinyl-3 (2H) -pyridazinone (8.0 g, 50 mmol, CASRN 6959-56-4), CuSO ₄ .5H ₂ O (26.12 g, 10.5 mmol) and H ₂ O (300 mL) were added and the mixture was stirred and heated to reflux overnight. The reaction was cooled to 0 ° C. and aqueous NaOH was added until the pH was 4. The aqueous layer was extracted twice with EtOAc (500 mL each). The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residual aqueous phase was adjusted to pH 2 with 37% HCl and the solution was extracted 6 times with EtOAc. The extracts were combined, dried (Na ₂ SO ₄ ), filtered and concentrated to give 4.75 g of 4-chloro-2H-pyridazin-3-one (75).

Step b-In a microwave vial, 75 (0.400 g, 3 mmol), bis- (pinacolato) diboron (0.934 g, 4 mmol), dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) [ 1,1′-biphenyl] -2-yl] -phosphine (X-Phos, 0.058 g, 0.12 mmol), Pd ₂ (dba) ₃ (0.056 g, 0.061 mmol) and KOAc (0.902 g, 9 mmol), the flask was evacuated and filled with Ar and sealed. Dioxane (6 mL) was added and the reaction was heated at 110 ° C. overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc (120 mL). The organic extract was washed sequentially with H ₂ O (10 mL) and brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was triturated with Et ₂ O to give 0.217 g of 78.

  Palladium-catalyzed coupling of 74b and 78 is performed as described in Example 14 to yield 76.

工程１ − 乾燥させたマイクロ波管をアルゴンでパージし、Ｐｄ_２（ｄｂａ）_３・ＣＨＣｌ_３（０．１１ｇ、０．１０６mmol）、２−ジ−tert−ブチルホスフィノ−２’，４’，６’−トリ−イソプロピル−１，１’−ビフェニル（０．１３６ｇ、０．３２１mmol）、ナトリウムtert−ブトキシド（０．１０ｇ、１．０４１mmol）、７４ｂ（０．３３ｇ、０．７１２mmol）及びtert−ブチルカーバメイト（０．１０ｇ、０．８５５mmol）を入れた。トルエン（３．５mL）を添加し、アルゴンを溶液に１時間バブリングすることにより得られた混合物を脱気した。管に蓋をし、反応混合物を室温で２日間撹拌した後、ＥｔＯＡｃで希釈し、飽和ＮＨ_４Ｃｌ水溶液で洗浄した。水層を、ＥｔＯＡｃで１回逆抽出した。合わせた有機層を、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。残渣を、ＳｉＯ_２フラッシュクロマトグラフィーによりヘキサン／ＥｔＯＡｃ（７．５／２．５）で溶離させて精製し、０．３１５ｇ（収率８９％）の８０ａを得た。 Example 17
N- {4- [6-tert-butyl-8- (2,4-dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl} -methanesulfonamide (I- 28)

Step 1—The dried microwave tube was purged with argon and Pd ₂ (dba) ₃ .CHCl ₃ (0.11 g, 0.106 mmol), 2-di-tert-butylphosphino-2 ′, 4 ′, 6′-tri-isopropyl-1,1′-biphenyl (0.136 g, 0.321 mmol), sodium tert-butoxide (0.10 g, 1.041 mmol), 74b (0.33 g, 0.712 mmol) and tert- Butyl carbamate (0.10 g, 0.855 mmol) was added. Toluene (3.5 mL) was added and the resulting mixture was degassed by bubbling argon through the solution for 1 hour. The tube was capped and the reaction mixture was stirred at room temperature for 2 days before being diluted with EtOAc and washed with saturated aqueous NH ₄ Cl. The aqueous layer was back extracted once with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by SiO ₂ flash chromatography eluting with hexane / EtOAc (7.5 / 2.5) to give 0.315 g (89% yield) of 80a.

Step 2-HCl (6 mL, 4 M in dioxane) was added to a solution of 80a (0.315 g, 0.631 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours and then concentrated. The residue was partitioned between saturated aqueous NaHCO ₃ and EtOAc. The aqueous layer was back extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give 80b, which was used in the next step without purification.

Step 3-Acrylic acid (0.09 mL, 1.304 mmol) was added to a solution of 80b (theoretically 0.631 mmol) in toluene (2.5 mL) at room temperature three times (0.02, 0.02, 0.05 mL). After the first addition, the reaction mixture was stirred at 120 ° C. for 2 hours. After the second addition, the reaction mixture was stirred at 120 ° C. for 1 hour, and after the third addition, the reaction mixture was stirred at 120 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was taken up in ice HOAc (2 mL) and urea (0.095 g, 1.576 mmol) was added. The reaction mixture was stirred at 120 ° C. for 6 hours, then cooled to room temperature and concentrated. The dark brown residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous layer was back extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was adsorbed on SiO _2, the SiO ₂ chromatography (SiO ₂ of 12 g) was purified by eluting with DCM / EtOAc gradient (50~80% EtOAc), gray tinged with I-28 of 0.07g green Obtained as a powder. The powder was taken up in a minimum amount of DCM and the insoluble material was filtered and rinsed with a small amount of DCM to give 0.04 g of I-28 as a light gray powder.

工程１ − Ｃｕ（Ｉ）（１０．０３ｇ）及びＣｓＦ（２１．４０ｇ）の混合物を、グローブバッグ中、窒素雰囲気下で、乳鉢で細かく粉砕し、自由流動性の粉末を得て、オーブンで乾燥させた、撹拌子及びセプタムを備えた２５０mLの丸底フラスコに移した。次に、フラスコに、２−ヨード−５−ニトロアニソール（１５．１７ｇ）及びスルホラン（３０mL）を入れ、４５℃で素早く撹拌した。混合物に、シリンジポンプを用いて、トリメチル（トリフルオロメチル）シラン（２０mL）を４時間かけて滴下し、得られた混合物を室温で一晩撹拌した。反応物をＥｔＯＡｃ（５００mL）で希釈し、いくらかのCELITE（登録商標）５１２で撹拌した。反応混合物を、CELITEパッドで濾過した。濾液をＥｔＯＡｃで１Ｌに希釈し、１Ｌの１０％ ＮＨ_４ＯＨ水溶液、１Ｌの１．０ＭのＨＣｌ及び５００mLの食塩水で洗浄した。有機相を乾燥させ（ＭｇＳＯ_４）、濾過して、真空で濃縮した。琥珀色の残渣をＤＣＭで希釈し、フラッシュクロマトグラフィー（７７０ｇのSupelco VersaPak（商標）ＳｉＯ_２カラム）によりＤＣＭ／ヘキサングラジエント（０〜４０％ ＤＣＭ）の１０カラム容積で溶離させて精製し、８．６１ｇの８２ｂを黄色の結晶固体として得た。 Example 18
N- {4- [8- (2,4-Dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-6-trifluoromethyl-quinolin-3-yl] -phenyl} -methanesulfonamide (I- 29)

Step 1—Cu (I) (10.03 g) and CsF (21.40 g) mixture were finely ground in a mortar in a glove bag under a nitrogen atmosphere to obtain a free-flowing powder and dried in an oven Transferred to a 250 mL round bottom flask equipped with a stir bar and septum. Next, 2-iodo-5-nitroanisole (15.17 g) and sulfolane (30 mL) were placed in the flask and stirred rapidly at 45 ° C. Trimethyl (trifluoromethyl) silane (20 mL) was added dropwise to the mixture using a syringe pump over 4 hours, and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (500 mL) and stirred with some CELITE® 512. The reaction mixture was filtered through a CELITE pad. The filtrate was diluted to 1 L with EtOAc and washed with 1 L of 10% aqueous NH ₄ OH, 1 L of 1.0 M HCl and 500 mL of brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. 7. The amber residue is diluted with DCM and purified by flash chromatography (770 g Supelco VersaPak ™ SiO ₂ column) eluting with 10 column volumes of DCM / hexane gradient (0-40% DCM); 61 g of 82b was obtained as a yellow crystalline solid.

Step 2-A 500 mL Parr hydrogenation flask was charged with 82b (8.60 g) and 10% Pd / C (1.75 g). The flask was purged with nitrogen and EtOH (150 mL) was carefully added. The mixture was purged with nitrogen for 5 minutes. Reduction was performed at 55 ° C. for 18 hours under a hydrogen pressure of 57 psi using a Parr shaker. The reaction mixture was cooled and the catalyst was filtered through a glass fiber filter and washed with IPA. The solvent was removed in vacuo. The crude material was diluted with DCM and purified by flash chromatography (200 g Analogix ™ SF65 SiO ₂ column) eluting with 15 column volumes of EtOAc / hexane gradient (0-40% EtOAc) to give 7.18 g of 84a was obtained as a waxy off-white solid.

Step 3-A 100 mL round bottom flask equipped with a stir bar and septum was charged with 84a (3.01 g) and maintained under a nitrogen atmosphere. To this flask was added anhydrous dioxane (25 mL) and HOAc (7.5 mL). The solution was stirred rapidly in an ice bath and a solution of bromine and dioxane (20 mL, 0.135 g Br ₂ / mL) was added dropwise over 30 minutes using a syringe pump. A beige precipitate formed and a viscous mixture was obtained. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of 1.0 M NaOH (150 mL) and 2.0 M Na ₂ CO ₃ (150 mL) and extracted with DCM (3 × 100 mL). The combined extracts were washed sequentially with 0.5M Na ₂ CO ₃ (150 mL) and brine (150 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting pale yellow liquid solidified slowly and darkened to give 84b (4.10 g) black crystalline solid.

Step 4-A 100 mL round bottom flask equipped with stir bar and septum was charged with HOAc (50 mL) and then 2-bromoacrolein (1.91 g) was added. Br ₂ (about 720 μL) was added dropwise to the stirred mixture until a red color was present. To this solution was added a solution of 84b (3.48 g) in HOAc (15 mL). A viscous precipitate formed and stirring was continued at 100 ° C. for 1 hour. The precipitate was dissolved and after 10 minutes a clear dark amber solution was obtained. A second precipitate formed after 30 minutes. The reaction was cooled to room temperature and poured into a stirred ice-cold solution of 2.0 M aqueous NaOH (550 mL). To this mixture was slowly added 2.0M Na ₂ CO ₃ aqueous solution until the pH of the solution was about 8 [foaming vigorously] and the resulting solution was extracted with DCM (3 × 250 mL). The combined extracts were washed with brine (500 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a dark resin which was flash chromatographed (385 g Supelco VersaPak). (Trademark) SiO ₂ column) eluting with 10 column volumes of DCM / hexane gradient (0-100% DCM). LC-MS and TLC analysis showed that the compound was not pure. The product was re-chromatographed (100 g Supelco VersaPak® SiO ₂ column) eluting with 30 column volumes of EtOAc / hexane gradient (0-100% EtOAc) to give 938 mg of 86 off-white. As a solid.

Step 5-In a 20 mL vial with stir bar and septum cap, add 86 (850 mg) and N-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl Methanesulfonamide (661 mg, CASRN 616880-14-9), dioxane (10 mL) and Cs ₂ CO ₃ aqueous solution (2.3 mL, 0.956 g Cs ₂ CO ₃ / mL) were added. The reaction mixture was sparged with nitrogen for 10 minutes before (dppf) PdCl ₂ · DCM (74 mg) was added. The reaction was sparged with nitrogen for 5 minutes, sealed and stirred at 65 ° C. for 110 minutes. The reaction was cooled and poured into DCM (100 mL) and 0.5 M aqueous Na ₂ CO ₃ (50 mL). The phases were separated, washed sequentially with H ₂ O (50 mL) and brine (50 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The product was purified by flash chromatography (100 g Supelco VersaPak® SiO ₂ column) eluting with 15 column volumes of EtOAc / DCM gradient (0-100% EtOAc) to obtain 538 mg of 88 light blue As a solid.

  Conversion of 88 to I-29 was performed according to steps 1 to 3 of Example 17.

  N- {4- [5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -6-trifluoromethyl-quinolin-3-yl] -phenyl}- Methanesulfonamide hydrobromide (I-49) was converted to N-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylmethanesulfone in Step 5. Prepared similarly except that the amide was replaced with 2-methoxy-6-methyl-pyridin-3-ylboronic acid. Demethylation of pyridinyl O-methyl ether can be carried out according to the procedure of Step 7 of Example 2.

  N- {4- [5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -6-trifluoromethyl-quinolin-3-yl] -phenyl}- The methanesulfonamide was the same except that in step 5, N-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylmethanesulfonamide was replaced with 115. Prepared. Demethylation of pyridinyl O-methyl ether can be carried out according to the procedure of Step 7 of Example 2.

  N- {4- [8- (2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-6-trifluoromethyl-quinolin-3-yl] -phenyl}- Methanesulfonamide (I-51) was prepared from 88 using the procedure of Example 3, Step 3.

工程１ − 乾燥させたマイクロ波管をアルゴンでパージし、８６（０．４７ｇ、１．２６mmol）、（Ｓ）−１−ピロリジン−３−イルメチル−カルバミン酸tert−ブチルエステル（０．３８ｇ、１．８９７mmol、CASRN 173340-26-6）、ナトリウムtert−ブトキシド（０．１８ｇ、１．８７３mmol）、xantphos（０．１４６ｇ、０．２５２mmol）及びＰｄ_２（ｄｂａ）_３（０）（０．１１５ｇ、０．１２６mmol）を入れた。管をアルゴンでパージし、１mLのトルエンを添加した。混合物にアルゴンを１５分間バブリングすることにより、反応混合物を脱気して、得られた混合物を１００℃で一晩撹拌し、室温に冷ました後、ＥｔＯＡｃ及び飽和ＮＨ_４Ｃｌ水溶液で分液した。水層を、ＥｔＯＡｃで２回逆抽出した。合わせた有機抽出物を、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。残渣を、ＳｉＯ_２クロマトグラフィー（４０ｇのＳｉＯ_２）によりＥｔＯＡｃ／ヘキサングラジエント（１０〜３０％ ＥｔＯＡｃ）で溶離させて精製し、０．２８ｇ（４５％）の９０ａを得た。 Example 19
N-{(S) -3- [6-tert-butyl-8- (dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -cyclopentyl} -methanesulfonamide (I- 31)

Step 1—The dried microwave tube was purged with argon and 86 (0.47 g, 1.26 mmol), (S) -1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester (0.38 g, 1 897 mmol, CASRN 173340-26-6), sodium tert-butoxide (0.18 g, 1.873 mmol), xantphos (0.146 g, 0.252 mmol) and Pd ₂ (dba) ₃ (0) (0.115 g, 0.126 mmol) was added. The tube was purged with argon and 1 mL of toluene was added. The reaction mixture was degassed by bubbling argon through the mixture for 15 minutes, and the resulting mixture was stirred at 100 ° C. overnight, cooled to room temperature, and then partitioned between EtOAc and saturated aqueous NH ₄ Cl. The aqueous layer was back extracted twice with EtOAc. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by SiO ₂ chromatography (40 g SiO ₂ ) eluting with an EtOAc / hexane gradient (10-30% EtOAc) to give 0.28 g (45%) of 90a.

Step 2-To a solution of 90a (0.32 g, 0.65 mmol) in DCM (2 mL) at room temperature was added HCl (2 mL, 4 M in dioxane). The resulting orange mixture was stirred at room temperature overnight and then concentrated. The light orange solid was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous layer was back extracted twice with EtOAc. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give 0.25 g of crude 90b, which was further purified using in the next reaction.

Step 3-Methanesulfonyl chloride (0.055 mL, 0.716 mmol) to a mixture of crude 90b (0.25 g, 0.637 mmol) and pyridine (0.062 g, 0.765 mmol) in DCM (3 mL) cooled to 0 <0> C. Was added. The resulting mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and 1M aqueous NaOH. The aqueous layer was back extracted twice with EtOAc. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by SiO ₂ chromatography (22 g SiO ₂ ) eluting with EtOAc / hexane (4/1) to give 0.12 g (40% yield) of 90c.

  Dioxo-tetrahydro-pyrimidin-1-yl was introduced according to the procedure described in Steps 1 to 3 of Example 18 to obtain I-31.

  N-{(S) -1- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -Pyrrolidin-3-ylmethyl} -methanesulfonamide (I-52) was obtained from 90c from 2,4-dioxo-3,4-dihydro-2H-pyrimidine-1- Prepared using the introduction procedure of

  N-{(S) -1- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -Pyrrolidin-3-ylmethyl} -methanesulfonamide HBr salt with a 6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl moiety as described in Step 1 of Example 1 It was prepared in the same manner except that it was introduced at the 8th position.

工程１ − 撹拌子及びキャップを備えた２５０mLの丸底フラスコに、９２ａ（９．９３ｇ）及び無水ＤＭＥ（１００mL）を入れ、撹拌して、清澄な黄色の溶液を得た。この溶液に、ＣＦ_３ＳｉＭｅ_３（９．０mL）、そして、ＣｓＦ（７９２mg）を順次添加した。反応混合物を２０分間超音波処理し、次に、室温でさらに４０分間撹拌した。２．０ＭのＨＣｌ溶液（１００mL）を添加し、得られた混合物を室温で１時間撹拌した。ＥｔＯＡｃ（２００mL）を添加し、相を分離した。有機相を飽和ＮａＨＣＯ_３水溶液（１５０mL）及び食塩水（１５０mL）で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、真空で濃縮した。粗生成物を、フラッシュクロマトグラフィー（３８５ｇのSupelco VersaPak（商標）ＳｉＯ_２カラム）によりＤＣＭ／ヘキサングラジエント（０〜１００％ ＤＣＭ）の５カラム容積で溶離させて精製した。回収した生成物をＤＣＭ（１００mL）に溶解させて、ヘキサン（２００mL）を添加した。溶媒の約２／３をロータリーエバポレーターでゆっくり除去した。得られた沈殿物を濾過し、ヘキサンで洗浄し、高真空下で乾燥させて、１３．１０ｇの９２ｂを白色固体として得た。 Example 20
N- {4- [8- (Dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-6- (2,2,2-trifluoro-ethyl) -quinolin-3-yl] -phenyl} -methane Sulfonamide (I-30)

Step 1-A 250 mL round bottom flask equipped with a stir bar and cap was charged with 92a (9.93 g) and anhydrous DME (100 mL) and stirred to give a clear yellow solution. To this solution was added CF ₃ SiMe ₃ (9.0 mL) and CsF (792 mg) sequentially. The reaction mixture was sonicated for 20 minutes and then stirred for an additional 40 minutes at room temperature. 2.0M HCl solution (100 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. EtOAc (200 mL) was added and the phases were separated. The organic phase was washed with saturated aqueous NaHCO ₃ (150 mL) and brine (150 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (385 g Supelco VersaPak ™ SiO ₂ column) eluting with 5 column volumes of DCM / hexane gradient (0-100% DCM). The collected product was dissolved in DCM (100 mL) and hexane (200 mL) was added. About 2/3 of the solvent was slowly removed on a rotary evaporator. The resulting precipitate was filtered, washed with hexane and dried under high vacuum to give 13.10 g of 92b as a white solid.

Step 2-A 1 L round bottom flask equipped with a stir bar, reflux condenser and nitrogen inlet was charged with 92b (13.01 g) and maintained under a nitrogen atmosphere. Anhydrous THF (300 mL) was added and the mixture was stirred to give a clear yellow solution. To this solution was added NaH (2.25 g, 60 wt% mineral oil dispersion) at room temperature. The mixture was sonicated for 20 minutes and stirred for an additional 10 minutes at room temperature. A solution of p-toluenesulfonyl chloride (11.86 g) and dry THF (100 mL) was added at room temperature and stirred at 50 ° C. for 90 minutes. The solution was cooled and poured into 0.5 M aqueous NaHCO ₃ (1 L). The reaction mixture was diluted with EtOAc (500 mL) and the organic phase was separated and washed with brine (500 mL), then dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was dissolved in DCM and chromatographed (385 g Supelco VersaPak ™ SiO ₂ column) eluting with 10 column volumes of DCM / hexane gradient (0-100% DCM). The light yellow resin was slowly crystallized to give 20.36 g of 92c as a white solid.

Step 3-92c (20.35 g) was placed in a Parr hydrogenation flask and dissolved in warm EtOH (200 mL) and the solid was washed in the flask with 50 mL EtOH. The solution was purged with nitrogen for 5 minutes while warming. 10% Pd / C (4.02 g) was added to the solution and the flask was flushed with nitrogen. The solution was hydrogenated using a Parr shaker under hydrogen at 55 psi at 50 ° C. for 1.5 hours. The catalyst was removed by filtration through a glass fiber filter and washed with warm EtOH (100 mL). The filtrate was concentrated on a rotary evaporator. The tosylate salt precipitated as a white solid. The residue was partitioned between 1.0 M aqueous NaOH (500 mL) and Et ₂ O (300 mL). The phases were separated and the aqueous phase was extracted with Et ₂ O (3 × 300 mL). The combined organic extracts were washed with brine (450 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (385 g Supelco VersaPak ™ SiO ₂ column) eluting with DCM to give 9.04 g of 94a as an off-white solid.

Step 4-A 250 mL round bottom flask equipped with a stir bar and septum was charged with 94a (8.16 g) and maintained under a nitrogen atmosphere. To the flask was added dry dioxane (100 mL) and HOAc (23 mL) and the solution was cooled to 5-10 ° C. with an ice bath. A solution of Br ₂ (7.03 g) in dioxane (45 mL) was added dropwise over 30 minutes using a syringe pump. A beige precipitate formed. The solution was warmed to room temperature and stirred for 1 hour, then poured into 1.0 M NaOH (500 mL) and extracted with DCM (3 × 300 mL). The combined extracts were washed with brine (450 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to give 11.42 g of 94b as a pale olive solid.

Step 5-A 40 mL vial with stir bar and septum was charged with 2-bromoacrolein (2.71 g) and HOAc (25 mL) was added. The solution was cooled in an ice / water bath and Br ₂ was added dropwise until the red color was maintained (approximately 1.0 mL). A few drops of 2-bromoacrolein were added until the solution was again colorless. This solution was poured into a stirred solution of 94b (5.67 g) and HOAc (25 mL) and the resulting mixture was stirred at 100 ° C. for 2 hours. The solution was cooled, diluted with H ₂ O (250 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were washed sequentially with 2.0 M aqueous NaOH (200 mL) and brine (150 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by chromatography (385 g Supelco VersaPak ™ SiO ₂ column) eluting with DCM to give 2.69 g of 96 as a light orange solid.

  The introduction of the 4-methanesulfonylaminophenyl substituent at the 3-position is carried out according to the procedure described in Step 5 of Example 19 and N- {4- [8-bromo-5-methoxy-6- (2,2,2). -Trifluoro-ethyl) -quinolin-3-yl] -phenyl} -methanesulfonamide (97) was obtained. Introduction of dioxo-tetrahydro-pyrimidin-1-yl at position 8 of 97 was carried out according to the procedure described in steps 1-3 of Example 18 to give I-30.

  N- {4- [5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -6- (2,2,2-trifluoro-ethyl) -quinoline -3-yl] -phenyl} -methanesulfonamide hydrobromide (I-53) was introduced from 96 using the procedure described in Example 5, Step 5, methanesulfonylamino-phenyl moiety, Thereafter, in step 3, the Suzuki cup according to steps 3 and 4 of Example 9, except that 2-methoxy-pyridin-3-ylboronic acid was replaced with 2-methoxy-6-methyl-pyridin-3-ylboronic acid. Prepared by sequential ring / demethylation.

  N- {4- [5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -6- (2,2,2-trifluoro-ethyl) -quinoline -3-yl] -phenyl} -methanesulfonamide (I-54) is prepared in the same manner except that 2-methoxy-pyridin-3-ylboronic acid was replaced with 115 in Step 3. Demethylation yielded the HBr salt in both cases.

  N- {4- [8- (2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-6- (2,2,2-trifluoro-ethyl) -quinoline -3-yl] -phenyl} -methanesulfonamide (I-56) is introduced in 97-position 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl of Example 23. It was prepared in the same manner except that it was carried out according to the procedure described in steps 1 to 3.

工程１ − ＣＤ_３ＯＤ（２５mL）及び４−ブロモフェノール（８．５ｇ、４９．２mmol）の溶液を室温で３０分間撹拌し、フェノール性プロトンを交換して、次に、ＣＤ_３ＯＤを真空で除去した。得られた固体を、ＣＤＣｌ_３（１０mL）及び（ＣＤ_３）_３ＣＯＤ（４mL）に溶解させ、６０℃に温めた。濃Ｄ_２ＳＯ_４（１０mL）を、５回に分けて（２mL×５）、５０分間かけて添加した。反応混合物を６０℃で一晩維持した後、氷（５０mL）に注ぎ、ＥｔＯＡｃ（２×７５mL）で抽出した。合わせた有機物を２ＮのＫＯＨ水溶液（３×３００mL）で抽出し、１ＮのＨＣｌ水溶液（７５mL）及び食塩水（２５mL）で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、真空で濃縮した。残渣を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサングラジエント（０〜１０％ ＥｔＯＡｃ、４０分間）で溶離させて精製し、５．８３ｇの９８ａを褐色の油状物として得た：ＥＳ ＭＳ（Ｍ-Ｈ）２３６．１． Example 21
N- {4- [6- [1,1-di (methyl-d ₃ ) ethyl-2,2,2-d ₃ ] -5-methoxy-8- (6-methoxy-2-oxo-1,2 -Dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide (I-32)

Step 1—A solution of CD ₃ OD (25 mL) and 4-bromophenol (8.5 g, 49.2 mmol) was stirred at room temperature for 30 minutes to exchange phenolic protons, and then CD ₃ OD was removed in vacuo. Removed. The resulting solid was dissolved in CDCl ₃ (10 mL) and (CD ₃ ) ₃ COD (4 mL) and warmed to 60 ° C. Concentrated D ₂ SO ₄ (10 mL) was added in 5 portions (2 mL × 5) over 50 minutes. The reaction mixture was kept at 60 ° C. overnight, then poured into ice (50 mL) and extracted with EtOAc (2 × 75 mL). The combined organics were extracted with 2N aqueous KOH (3 × 300 mL), washed with 1N aqueous HCl (75 mL) and brine (25 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-10% EtOAc, 40 min) to give 5.83 g of 98a as a brown oil: ES MS (M−H) 236.1.

Step 2 2- (D ₉ -tert-butyl) -4-bromophenol (98a, 35.1 g, 147 mmol) and TEA (17.9 g, 177 mmol) in Et ₂ O (285 mL) maintained at 0 ° C. in an ice bath. ) To the solution, ethyl chloroformate (18.4 g, 16.3 mL, 169 mmol) was added dropwise over 10 minutes. After about 5 minutes, a white precipitate was observed. The reaction was maintained at 0 ° C. with vigorous stirring for 3 hours. The mixture was diluted with saturated aqueous NH ₄ Cl (100 mL) and the layers were separated. The aqueous layer was washed with Et ₂ O (100 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-10% EtOAc, 45 min) to give 36.5 g of 98b as a brown oil: ES MS (M + H) 310. 1

Step 3-To a solution of 98b (36 g, 116 mmol) in concentrated sulfuric acid (147 g, 80 mL, 1.5 mol) cooled to 0 ° C, 70% HNO ₃ (8.77 g, 6.22 mL, 139 mmol) was added dropwise over 10 minutes. did. The reaction was maintained at 0 ° C. for 2 hours and then poured onto ice (ca. 500 g). The aqueous solution was extracted with 1: 1 EtOAc / hexane (3 × 200 mL) and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated with SiO ₂ (100 g). The product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-10% EtOAc, 45 min) to give 35.8 g of 100a as a yellow solid: ES MS (M + H) 355. 1

Step 4-Solid pellet of KOH (8.29 g, 148 mmol) was added to a solution of 100a (35.0 g, 98.5 mmol) in MeOH (800 mL) over 1 min and the resulting solution was placed in a water bath at room temperature. Left overnight. MeOH was removed in vacuo and the residue was dissolved in DCM (150 mL). The organic solution was washed with 2N HCl (200 mL) and the aqueous layer was back extracted with DCM (50 mL). The combined extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give 27.8 g of 100b as a viscous orange liquid that was further purified without further purification. Used in the process: ES MS (M-H) 281.1

Step 5 - iodomethane (17.4g, 7.67mL, 123mmol) was added to a solution, 100b (27.8 g, 98.2 mmol) and _{K 2 CO 3 (20.4g, 147mmol} ) of acetone (110 mL) suspension of It was dripped in. The red suspension was stirred vigorously at room temperature for 16 hours. Ice water (500 mL) was added resulting in a fine yellow precipitate. The mixture was stirred for 30 minutes, filtered and the solid washed with H ₂ O (150 mL). The solid was dried overnight at 40 ° C. under vacuum to give 24.8 g of 100c, which was used without further purification: ES MS (M + H) 297.1

Step 6 - three-necked flask 1L, 100c (24g, 80.8mmol) , iron powder (22.5g, 404mmol) and _{NH 4 Cl (21.6g, 404mmol)} , EtOH (200mL) and _H 2 O (200mL) Put. The flask was fitted with a condenser and the yellow suspension was heated to 70 ° C. and stirred vigorously with a mechanical stirrer for 15 hours. The reaction was cooled to room temperature and filtered through CELITE. The CELITE pad was washed with MeOH (about 100 mL). Much of MeOH and EtOH were removed in vacuo. The aqueous mixture was extracted with EtOAc (3 × 100 mL). The combined extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 21.1 g of 102 as a light brown oil. This was allowed to solidify and was used without further purification: ES MS (M + H) 267.1

The conversion of 102 to I-32 was performed according to the procedure described in steps 2-5 of Example 9, except that 2,6-dimethoxy-pyridin-3-ylboronic acid was used in step 3 instead of 59. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ d 10.0 (br s, 1 H), 9.12 (d, J = 2.3 Hz, 1 H), 8.54 (d, J = 2.3 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 2 H), 7.60 (s, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 6.31 (br s, 1 H), 4.00 (s, 3 H) , 3.87 (s, 3 H), 3.04 (s, 3 H)

２，７−ジブロモ−２−tert−ブチル−３，４−ジヒドロ−２Ｈ−ナフタレン−１−オン（１１０）：
工程ａ − （７−ブロモ−３，４−ジヒドロナフタレン−１−イルオキシ）トリメチルシラン（６．８５ｇ、１１．５mmol、CASRN 309929-09-7）及びＤＣＭ（２３．０mL）の溶液を−４０℃に冷却した。２−クロロ−２−メチルプロパン（１．１２ｇ、１．３２mL、１２．１mmol）を添加し、溶液を窒素下で撹拌した。溶液を−４０℃に維持しながら、ＴｉＣｌ_４（２．１９ｇ、１．２７mL、１１．５mmol）のＤＣＭ（６mL）溶液を滴下した。添加完了の直後のＴＬＣから、変換が約５０％行われたことが分かった。反応物を、室温で週末にかけて撹拌した後、氷に注いだ。混合物をＥｔＯＡｃ及びＨ_２Ｏで分液し、水層を飽和ＮａＨＣＯ_３水溶液で中和した。混合物をCELITEプラグで濾過して、塊の白色の沈殿物を除去した。有機層を分離して、食塩水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗生成物をヘキサンで平衡化したＳｉＯ_２カラムに装填し、ＥｔＯＡｃ／ヘキサングラジエント（０〜５％ ＥｔＯＡｃ）で溶離させて、３．２６ｇ（定量的）の７−ブロモ−２−tert−ブチル−３，４−ジヒドロ−２Ｈ−ナフタレン−１−オン（１０９）を黄色の固体として得た。 Example 22
N- {4- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl}- Methanesulfonamide (I-34)

2,7-Dibromo-2-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (110):
Step a— A solution of (7-bromo-3,4-dihydronaphthalen-1-yloxy) trimethylsilane (6.85 g, 11.5 mmol, CASRN 309929-09-7) and DCM (23.0 mL) was added at −40 ° C. Cooled to. 2-Chloro-2-methylpropane (1.12 g, 1.32 mL, 12.1 mmol) was added and the solution was stirred under nitrogen. A solution of TiCl ₄ (2.19 g, 1.27 mL, 11.5 mmol) in DCM (6 mL) was added dropwise while maintaining the solution at −40 ° C. TLC immediately after the addition was complete indicated that conversion was about 50%. The reaction was stirred at room temperature over the weekend and then poured onto ice. The mixture was partitioned between EtOAc and H ₂ O and the aqueous layer was neutralized with saturated aqueous NaHCO ₃ . The mixture was filtered through a CELITE plug to remove lumpy white precipitate. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude product was loaded onto a SiO ₂ column equilibrated with hexane and eluted with an EtOAc / hexane gradient (0-5% EtOAc) to give 3.26 g (quantitative) of 7-bromo-2-tert-butyl- 3,4-Dihydro-2H-naphthalen-1-one (109) was obtained as a yellow solid.

Step b—To a stirred solution of 109 (3 g, 10.7 mmol) and HOAc (40 mL) was added a solution of bromine (1.88 g, 605 μL, 11.7 mmol) in HOAc (20.0 mL) at room temperature under N _2. It was dripped over 20 minutes with a cannula. After the solution was stirred at room temperature for 1 hour, the reaction was warmed to 50 ° C. and stirred for 1 hour. An aliquot of stock bromine (100 μL) was added and heating was continued. The total heating time was 2.5 hours. The reaction mixture was poured into ice, was separated with EtOAc and _{H 2} O, the aqueous phase was neutralized with saturated aqueous NaHCO _3. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated. The product was purified by SiO ₂ chromatography eluting with hexanes to give 3.8 g (quantitative) of 110.

Step 1 - To a round bottom flask, 110 (3.8g, 10.6mmol), LiBr (275mg, 3.17mmol), Li 2 CO 3 (780mg, 10.6mmol) and placed DMF (44.0 mL), white Ar was bubbled into the suspension for 10 minutes. The suspension was heated at 100 ° C. under N ₂ for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc, washed three times with water, then brine, then dried (MgSO ₄ ), filtered and concentrated to give 112a as a light brown viscous oil. It was. This was used without further purification.

Step 2-MeI (1.77 g, 779 μL, 12.5 mmol) was added to a solution of 112a (2.9 g, 10.4 mmol) and K ₂ CO ₃ (3.59 g, 26.0 mmol) in DMF (29.7 mL). Upon addition, the mixture was capped and stirred at 25 ° C. overnight. The mixture was diluted with EtOAc and water and the aqueous phase was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated to give 112b. This was used without further purification.

Step 3—To a solution of 112b (1.6 g, 5.46 mmol) and HOAc (30 mL) maintained under nitrogen, a solution of bromine (872 mg, 281 μL, 5.46 mmol) in HOAc (20 mL) was added dropwise via an addition funnel. . The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water and the aqueous phase was neutralized with saturated aqueous NaHCO ₃ solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated to give 112c. This was used without further purification.

Step 4 - microwave tube 2~5mL, 112c (1g, 2.69mmol) , 25 (578mg, 2.69mmol), Na 2 CO 3 (855mg, 8.06mmol), MeOH (7.14mL), toluene (3.57 mL) and H ₂ O (1.79 mL) were added. The mixture was degassed with argon for 10 minutes and then Pd (PPh ₃ ) ₄ (155 mg, 134 μmol) was added. Degassing was continued for an additional 5 minutes, after which the vial was sealed and heated at 115 ° C. for 1.5 hours. The mixture was cooled, partitioned between EtOAc and water, and the aqueous phase was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (20-50% EtOAc) to give 0.67 g (54%) of 114 as a white solid.

Step 5—Into a 2-5 mL microwave tube, 114 (0.08 g, 173 μmol), 2,6-dimethoxypyridin-3-ylboronic acid (115, 34.8 mg, 190 μmol) and Na ₂ CO ₃ (55.0 mg) 519 μmol), MeOH (1.5 mL), toluene (750 μL) and H ₂ O (165 μL). The mixture was degassed with argon for 10 minutes, then Pd (PPh ₃ ) ₄ (10.0 mg, 8.65 μmol) was added and degassing continued for another 5 minutes. The vial was sealed and irradiated by a microwave reactor at 115 ° C. for 20 minutes. The mixture was cooled, diluted with EtOAc and H ₂ O, and the aqueous phase was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by preparative SiO ₂ TLC plate developed with 40% EtOAc / hexanes to give 82 mg (92%) of 116 as a light brown foam.

Step 6—The vial was charged with 116 (0.082 g), HBr (53.1 mg, 35.6 μL, 315 μmol) and HOAc (0.75 mL), flushed with argon and sealed. The sealed mixture was heated at 55 ° C. for 6 hours. The reaction was cooled, diluted with EtOAc and poured onto ice. The resulting solution was neutralized with saturated aqueous NaHCO ₃ solution. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by developing with 50% EtOAc / hexanes on SiO ₂ plates to give 44 mg of I-34.

工程１ − １０〜２０mLのマイクロ波管に、１１４（０．３５ｇ、０．７５７mmol）、tert−ブチルカーバメイト（１２４mg、１．０６mmol）及びナトリウムtert−ブトキシド（１０７mg、１．１１mmol）、そして、トルエン（６．００mL）を入れると、白色の懸濁液が生じた。混合物を、アルゴンで１０分間フラッシュした。非常に粘性の高い混合物をトルエン（４mL）で希釈し、次に、Ｐｄ_２（ｄｂａ）_３（１０４mg、１１４μmol）及び２−ジ−tert−ブチルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル（１４５mg、３４１μmol）を添加し、混合物にアルゴンを５分間バブリングした。反応物を、密封バイアル中、室温で週末にかけて撹拌した。混合物をＥｔＯＡｃ及びＨ_２Ｏで分液し、水溶液を１ＮのＨＣｌで中和した。有機層を分離して、食塩水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、真空で濃縮した。粗生成物を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサングラジエント（２０〜６０％ ＥｔＯＡｃ）で溶離させて精製し、１９６mg（５２％）の１１６ａを得た。 Example 23
N- {4- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide (I-35)

Step 1-To a 10-20 mL microwave tube, add 114 (0.35 g, 0.757 mmol), tert-butyl carbamate (124 mg, 1.06 mmol) and sodium tert-butoxide (107 mg, 1.11 mmol) and toluene (6.00 mL) was added, resulting in a white suspension. The mixture was flushed with argon for 10 minutes. The very viscous mixture was diluted with toluene (4 mL) and then Pd ₂ (dba) ₃ (104 mg, 114 μmol) and 2-di-tert-butylphosphino-2 ′, 4 ′, 6′-tri Isopropyl biphenyl (145 mg, 341 μmol) was added and argon was bubbled through the mixture for 5 minutes. The reaction was stirred in a sealed vial over the weekend at room temperature. The mixture was partitioned between EtOAc and H ₂ O and the aqueous solution was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (20-60% EtOAc) to afford 196 mg (52%) of 116a.

Step 2-A 25 mL pear-shaped flask was charged with 116a (0.196 g, 197 μmol), DCM (1.5 mL) and 4M HCl-dioxane (491 μL, 1.97 mmol), and then stirred at room temperature for 3 hours. When all the starting material disappeared, the solution was diluted, poured onto ice and neutralized with saturated aqueous NaHCO ₃ solution. The mixture was concentrated and purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (20-50% EtOAc) to afford 116b. This was used without further purification.

Step 3-A small flask covered with foil was charged with cyanato silver (135 mg, 903 μmol) and heated at 50 ° C. under high vacuum overnight. To the obtained solid, dry toluene (1.29 mL) and (E) -3-methoxyacryloyl chloride (65.3 mg, 542 μmol) were sequentially added. The resulting slurry was heated at 120 ° C. for 30 minutes under nitrogen. After the mixture was cooled to room temperature, it was immersed in an ice bath to precipitate a solid. In a separate dry flask, 116b (0.072 g, 181 μmol) was dissolved in DMF (1.03 mL) and cooled to 0 ° C. The supernatant of the cyanate silver flask was added dropwise to the DMF solution over 10 minutes. A light brown heterogeneous mixture formed after the addition and was stirred in an ice bath for 30 minutes. The mixture was diluted with EtOAc and washed sequentially with H ₂ O and brine. The presence of the intermediate urea was confirmed by NMR and was a mixture of cis and trans isomers. Urea was taken up in EtOH (1.03 mL) and a solution of 11% H ₂ SO ₄ in H ₂ O (1.03 mL) was added. The resulting mixture was placed in a vial, sealed and heated at 120 ° C. for 1.5 hours until the solution was homogeneous. The mixture was cooled, poured into ice and diluted with EtOAc. The organic phase was diluted with EtOAc, washed sequentially with H ₂ O and brine, dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (50-100% EtOAc) to give approximately 60 mg of 1-35 as a yellow solid.

工程１ − １０〜２０mLのマイクロ波管に、（Ｓ）−７２（１８４mg、１．０３mmol）及びトルエン（４．６９mL）を入れ、褐色の溶液を得た。これに、１１２ｃ（３４９mg、９３８μmol）及びトルエン（４．６９mL）を添加した。アルゴンを溶液に１０分間バブリングし、次に、Ｐｄ_２（ｄｂａ）_３（８５．９mg、９３．８μmol）及びXANTPHOS（１０９mg、１８８μmol）を添加した。脱気を５分間続け、その後、ナトリウムtert−ブトキシド（１３５mg、１．４１mmol）を素早く添加して、溶液をアルゴンでフラッシュして密封した。溶液を、マイクロ波シンセサイザーにより１００℃で１０分間照射し、次に、室温で一晩撹拌した。ＤＭＳＯをいくらか添加し、固体を溶解させて、バイアルを３時間加熱した。混合物を冷却し、ＥｔＯＡｃ及び水で希釈し、水層を１ＮのＨＣｌで中和した。有機層を分離して、食塩水で洗浄し、乾燥させ（ＭｇＳＯ_４）、濾過して、真空で濃縮した。粗生成物を、分取ＳｉＯ_２ＴＬＣプレートにより５０％ ＥｔＯＡｃ／ヘキサンで２回展開させて精製し、９２mgの１１８を得た。生成物をさらに精製することなく使用した。 Example 24
N-{(S) -1- [7-tert-butyl-8-methoxy-5- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -naphthalen-2-yl] -Pyrrolidin-3-ylmethyl} -methanesulfonamide (I-36)

Step 1-A 10-20 mL microwave tube was charged with (S) -72 (184 mg, 1.03 mmol) and toluene (4.69 mL) to give a brown solution. To this was added 112c (349 mg, 938 μmol) and toluene (4.69 mL). Argon was bubbled through the solution for 10 minutes, then Pd ₂ (dba) ₃ (85.9 mg, 93.8 μmol) and XANTPHOS (109 mg, 188 μmol) were added. Degassing was continued for 5 minutes, after which sodium tert-butoxide (135 mg, 1.41 mmol) was quickly added and the solution was flushed with argon and sealed. The solution was irradiated with a microwave synthesizer at 100 ° C. for 10 minutes and then stirred overnight at room temperature. Some DMSO was added to dissolve the solid and the vial was heated for 3 hours. The mixture was cooled, diluted with EtOAc and water, and the aqueous layer was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by preparative SiO ₂ TLC plate developed twice with 50% EtOAc / hexanes to give 92 mg of 118. The product was used without further purification.

Step 2—To a 2-5 mL microwave tube, add 118 (85 mg, 181 μmol), 115 (39.8 mg, 217 μmol), Na ₂ CO ₃ (57.6 mg, 543 μmol), MeOH (0.4 μL), toluene (0 ₂ μL) and H ₂ O (0.2 μL). The mixture was bubbled with argon for 10 minutes and then Pd (PPh ₃ ) ₄ (10.5 mg, 9.05 μmol) was added. The solution was bubbled with argon for an additional 5 minutes. The vial was sealed and irradiated by a microwave reactor at 115 ° C. for 20 minutes. The mixture was cooled, diluted with EtOAc and water, and the aqueous layer was neutralized with 1N HCl. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (25-50% EtOAc) to give 56.6 mg of 120.

Step 3— Ether was demethylated as described in Step 6 of Example 22 to give pyridone. The crude product was purified by eluting with EtOAc / hexane gradient (50 to 75% EtOAc) by SiO ₂ chromatography to afford I-36 as an off-white solid.

工程１ − 臭素（４．４８mL、８６．９mmol）のＨＯＡｃ（５０mL）溶液を、室温で、溶液がわずかなＢｒ_２の色を示すまで、２−ブロモアクリルアルデヒド（１１．７ｇ、８６．９mmol、CASRN 111049-68-4）のＨＯＡｃ（１００mL）溶液に添加した。この溶液に、４−アミノ−５−ブロモ−２−メトキシ安息香酸メチル（２２．６ｇ、８６．９mmol）を添加し、得られた溶液を１００℃に徐々に加熱した。温度が１００℃に達した後、１５分間撹拌を続け、次に、溶液を冷却し、真空で濃縮した。反応混合物を飽和ＮａＨＣＯ_３水溶液で中和し、得られた固体を濾過して、水で洗浄した。固体をエーテル、その後、１０％ ＭｅＯＨ／ＤＣＭで洗浄し、１１．０４ｇの１２２ａを得た。濾液をＳｉＯ_２に吸着させ、フラッシュカラムでＤＣＭ／ヘキサングラジエント（５０〜１００％ ＤＣＭ）で溶離させて精製し、追加の３．４６ｇの１２２ａを得た。 Example 25
N- {4- [6- (1-difluoromethyl-cyclopropyl) -5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoline-3- Yl] -phenyl} -methanesulfonamide (I-37)

Step 1—A solution of bromine (4.48 mL, 86.9 mmol) in HOAc (50 mL) was added 2-bromoacrylaldehyde (11.7 g, 86.9 mmol, at room temperature until the solution showed a slight Br ₂ color. CASRN 111049-68-4) was added to a HOAc (100 mL) solution. To this solution was added methyl 4-amino-5-bromo-2-methoxybenzoate (22.6 g, 86.9 mmol) and the resulting solution was gradually heated to 100 ° C. After the temperature reached 100 ° C., stirring was continued for 15 minutes, then the solution was cooled and concentrated in vacuo. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ and the resulting solid was filtered and washed with water. The solid was washed with ether and then 10% MeOH / DCM to give 11.04 g of 122a. The filtrate was adsorbed onto SiO ₂ and purified on a flash column eluting with a DCM / hexane gradient (50-100% DCM) to give an additional 3.46 g of 122a.

Step 2-DIBAL (9.22 g, 64.38 mmol) was added dropwise to a heterogeneous 122a (11.05 g, 29.5 mmol) in DCM (550 mL) at 0 ° C. The reaction was complete when the addition was complete. The reaction was quenched with aqueous Rochelle salt solution and partitioned between H ₂ O and DCM. The organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was adsorbed onto SiO ₂ and purified by flash chromatography eluting with a DCM / MeOH gradient (0-10% MeOH) to give 9.5 g of 122b.

Step _{3 - 122b (7.82g, 22.5mmol)} , CBr 4 (8.97g, 1.2 _{eq), Ph 3 P (7.09g,} 1.2 eq) and a solution of DCM (250 mL) at room temperature Stir overnight. The next morning, 0.5 equivalents of CBr ₄ and PPh ₃ were added. The reaction was complete after 1 hour. The crude reaction mixture was concentrated in vacuo. The crude product was adsorbed onto SiO ₂ and purified by flash chromatography eluting with a DCM / hexane gradient (0-100% DCM) to give 7.62 g of 122c as a white solid.

Step 4 - 122c (8.00g, 19.1mmol) , KCN (12.4g, 191mmol), a solution of DCM (156 mL) and _H 2 O (140mL), and heated to reflux for 15 minutes. The reaction mixture was diluted with H ₂ O and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dry loaded onto a SiO ₂ flash chromatography column and purified by flash chromatography eluting with a MeOH / DCM gradient (0-5% MeOH) to give 122d as a white solid.

Step 5- A mixture of 122d (5.02 g, 14.1 mmol), 1,2-dibromoethane (3.18 g, 1.46 mL, 16.9 mmol) and DMF (60 mL) was cooled to 0 ° C. and NaH (1 .69 g, 42.3 mmol, 60% mineral oil dispersion) was added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with H ₂ O and extracted with DCM. The organic layer was washed twice with H ₂ O, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was dry loaded onto SiO ₂ and purified by flash chromatography eluting with a DCM / hexane gradient (0-100% DCM) to give 1.91 g of 124a.

Step 6-To a solution of 124a (0.28 g, 0.733 mmol) in DCM (14 mL) was added DIBAL (870 [mu] L, 0.879 mmol, 1 M DCM solution) dropwise at -78 [deg.] C. The reaction mixture was stirred at −78 ° C. for 1 hour. The reaction was quenched with aqueous Rochelle salt solution and extracted with DCM. The organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by flash chromatography to give 0.22 g of 124b as a white solid.

Step 7-To a solution of 124b (0.63 g, 1.64 mmol) in DCM (14.3 mL) was added DAST (1.05 g, 6.54 mmol) and the resulting solution was stirred for 72 h. The reaction mixture was diluted with H ₂ O and extracted with DCM. The organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with a DCM / hexane gradient (50-100% DCM) to give 0.60 g of 124c as a white solid.

  Steps 8 to 10 were performed according to the procedure of Steps 4 to 6 in Example 22 except that 115 was replaced with 75 in Step 5.

  N- {4- [6- (1-difluoromethyl-cyclopropyl) -5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoline-3- Yl] -phenyl} -methanesulfonamide (I-38) was prepared similarly except that 115 was replaced with 75 in step 5.

  N- {4- [6- (1-difluoromethyl-cyclopropyl) -8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinoline-3- Yl] -phenyl} -methanesulfonamide (I-39) was prepared from 124c according to steps 1 to 3 of Example 23 by introducing uracil.

２，４−ジメトキシ−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリミジン（１１７）
２５０mLの丸底フラスコに、５−ブロモ−２，４−ジメトキシピリミジン（１．２３ｇ、５．６２mmol）、ＰｄＣｌ_２（ｄｐｐｆ）．ＣＨ_２Ｃｌ_２（２２９mg、２８１μmol）、ビス−（ピナコラト）ジボロン（１．７１ｇ、６．７４mmol）、ＫＯＡｃ（１．６５ｇ、１６．８mmol）及びＤＭＦを入れた。明黄色の溶液を１００℃に加熱し、１時間撹拌した。反応混合物を５０mLのＨ_２Ｏに注ぎ、ＥｔＯＡｃ／トルエン（１：１、３×５０mL）で抽出した。有機層を合わせ、Ｈ_２Ｏ（１×５０mL）、飽和ＮａＣｌ水溶液（５０mL）で洗浄した。有機層を乾燥させて（Ｎａ_２ＳＯ_４）、濾過して、真空で濃縮し、１１７（１．６７ｇ、７８％）及び回収臭化物の７：３混合物を得た。暗色の固体を、さらに精製することなく次の工程で使用した。 Example 26
N-{(S) -1- [6-tert-butyl-5-methoxy-8- (1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)- Quinolin-3-yl] -pyrrolidin-3-ylmethyl} -methanesulfonamide (I-40)

2,4-Dimethoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (117)
A 250 mL round bottom flask was charged with 5-bromo-2,4-dimethoxypyrimidine (1.23 g, 5.62 mmol), PdCl ₂ (dppf). CH ₂ Cl ₂ (229 mg, 281 μmol), bis- (pinacolato) diboron (1.71 g, 6.74 mmol), KOAc (1.65 g, 16.8 mmol) and DMF were added. The light yellow solution was heated to 100 ° C. and stirred for 1 hour. The reaction mixture was poured into 50 mL H ₂ O and extracted with EtOAc / toluene (1: 1, 3 × 50 mL). The organic layers were combined and washed with H ₂ O (1 × 50 mL), saturated aqueous NaCl (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 117 (1.67 g, 78%) and a 7: 3 mixture of recovered bromide. The dark solid was used in the next step without further purification.

Step 1—Into a tube with a 10 mL screw cap, N-[(S) -1- (5-bromo-7-tert-butyl-8-methoxy-naphthalen-2-yl) -pyrrolidin-3-ylmethyl]- Methanesulfonamide (118, 0.188 g, 400 μmol), PdCl ₂ (dppf). Put CH ₂ Cl ₂ (16.3 mg, 20.0 μmol), Cs ₂ CO ₃ (391 mg, 1.2 mmol) and 117 (182 mg, 480 μmol), dioxane (3.2 mL) and H ₂ O (799 μL) in the dark. A brown solution was obtained. The reaction mixture was heated to 100 ° C. and stirred for 30 minutes. The reaction mixture was poured into 50 mL H ₂ O and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with H ₂ O (50 mL) and brine (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with a MeOH / DCM gradient (0% to 5% MeOH) to give 0.077 g (36%) of 120 as a solid.

Step 2-A 10 mL tube with a screw cap was charged with 120 (0.055 g, 104 μmol), MeI (250 mg, 0.11 mL, 1.76 mmol) and DCM (0.11 mL). The light yellow solution was stirred for 5 hours and then concentrated. The crude material was purified by SiO ₂ chromatography eluting with a DCM / hexane gradient (0-6% MeOH) to yield 0.022 g (40%) of (S) -N-((1- (6-tert- Butyl-5-methoxy-8- (4-methoxy-1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl) quinolin-3-yl) pyrrolidin-3-yl) methyl) methanesulfonamide ( 122) was obtained as a solid.

Step 3-A 10 mL tube with a screw cap was charged with 122 (0.021 g, 39.6 μmol), HBr (16.0 mg, 10.8 μL, 198 μmol) and HOAc. After 4 hours, the reaction mixture was poured into saturated aqueous NaHCO ₃ (50 mL) and extracted with EtOAc (3 × 20 mL). The organic extracts were dried _(Na 2 _SO 4), filtered, and concentrated to give I-40 in 0.020 g (98%) as a yellow solid.

  N- {4- [6-tert-butyl-5-methoxy-8- (1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -quinoline-3- Yl] -phenyl} -methanesulfonamide was prepared from 114 using the procedure of steps 1-3 of this example.

Example 27
N- {4- [6-tert-butyl-8- (5-chloro-6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -Phenyl} -methanesulfonamide (I-42)
The hydrobromide salt of I-24 (34 mg, 0.059 mmol) was neutralized with saturated aqueous NaHCO ₃ to give the free base, which was extracted with EtOAc. The EtOAc extract was dried (MgSO ₄ ), filtered and concentrated. The residue was dissolved in MeCN (1 mL) and DMF (1 mL) and warmed to 60 ° C. NCS (8 mg, 0.06 mmol) was then added to the reaction mixture. After stirring at 60 ° C. for 1.5 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with 9: 1 DCM / MeOH to give 8 mg (49%) of I-42 as a white solid. MS m / z (ES): 527 (M + H) ⁺

工程１ − 管に、７０（２０８mg、０．５８２mmol）、２−アミノ−ピリジン−５−イルボロン酸（２２７mg、０．８４mmol）、Ｐｄ（ＰＰｈ_３）_４（６１mg、０．０５２mmol）、Ｎａ_２ＣＯ_３（２８６mg、２．６９mmol）、ＭｅＯＨ（１．６mL）及びＤＣＭ（０．５mL）を入れ、密封し、マイクロ波反応器により１１５℃で１時間照射した。反応混合物を室温に冷まし、ＥｔＯＡｃで希釈した。有機層を飽和ＮａＨＣＯ_３水溶液（３０mL）で洗浄した。有機相を分離し、水相をＥｔＯＡｃ（３×３０mL）で再抽出した。合わせた有機抽出物を、乾燥させ（ＭｇＳＯ_４）、濾過して、濃縮した。粗残渣を、ＳｉＯ_２クロマトグラフィーによりＤＣＭ／ＭｅＯＨグラジエントで溶離させて精製し、１７３mg（７１％）のＩ−４３を白色固体として得た。 Example 28
3- [3- (6-Amino-pyridin-3-yl) -6-tert-butyl-5-methoxy-quinolin-8-yl] -1H-pyridin-2-one (I-43)

Step 1—To the tube, 70 (208 mg, 0.582 mmol), 2-amino-pyridin-5-ylboronic acid (227 mg, 0.84 mmol), Pd (PPh ₃ ) ₄ (61 mg, 0.052 mmol), Na ₂ CO ₃ (286 mg, 2.69 mmol), MeOH (1.6 mL) and DCM (0.5 mL) were sealed and irradiated by a microwave reactor at 115 ° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ (30 mL). The organic phase was separated and the aqueous phase was re-extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by SiO ₂ chromatography eluting with a DCM / MeOH gradient to give 173 mg (71%) of I-43 as a white solid.

  5- {5- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -pyridin-2-yl} methane The sulfonamide (124) can be prepared by sulfonylating I-43 with methanesulfonyl chloride according to the procedure of Step 2 of Example 5.

３−（３−ブロモ−６−tert−ブチル−５−メトキシ−キノリン−８−イル）−６−メチル−１Ｈ−ピリジン−２−オン（１２８）は、工程３で、３０を７５に交換した以外は実施例９の工程１〜４で用いられる手順に従って、調製することができ、これにより７０を調製することができる。 Example 29
N- {4- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -butyl}- Methanesulfonamide (I-44)

3- (3-Bromo-6-tert-butyl-5-methoxy-quinolin-8-yl) -6-methyl-1H-pyridin-2-one (128) was exchanged 30 to 75 in step 3. Can be prepared according to the procedure used in steps 1 to 4 of Example 9, whereby 70 can be prepared.

Step 1-1 A THF (30 mL) mixture of 1-butynol (0.5 g, 7.13 mmol), MsNHBoc (2.09 g, CASRN 147741-16-4), PPh ₃ (2.8 g) was cooled in an ice bath, DEAD (1.86 g) was added. The mixture was stirred overnight and then concentrated in vacuo. The residue was triturated with Et ₂ O and the solid was filtered. The filtrate was concentrated and the process was repeated. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-10% EtOAc) to give 1.0 g of 126.

Step 2—To the tube, 128 (0.25 g, 0.62 mmol), 126 (0.3 g, 1.25 mmol), CuI (12 mg), Pd (PPh ₃ ) ₄ (0.072 mg), TEA (0.5 mL) ) And DMF, sealed and heated at 90 ° C. overnight. The tube was cooled and the reaction mixture was diluted with EtOAc, washed sequentially with H ₂ O and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (50-100% EtOAc). The residue was dissolved in DCM, TFA (1 mL) was added and the resulting solution was stirred at room temperature overnight. The solvent is evaporated and the residue is eluted with an EtOAc / hexane gradient (50-100% EtOAc) by SiO ₂ chromatography and then again with a MeOH / EtOAc gradient (0-8% MeOH) by chromatography. To obtain 80 mg of 130.

Step 3- A Parr flask was charged with 130 (60 mg, 128 μmol), Pd / C (13.7 mg) and a mixture of EtOAc and MeOH and hydrogenated under 50 psi of hydrogen for 20 hours. An additional aliquot of Pd / C (13 mg) was added and hydrogenation continued for 72 hours. The reaction mixture was filtered through CELITE, washed with DCM and the filtrate was concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with a MeOH / EtOAc gradient (0-10% MeOH) to give 30 mg of I-44.

  N- {3- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -propyl}- Methanesulfonamide was prepared in the same manner except that in step 2, palladium-catalyzed amination was performed with 3-propynylmethanesulfonamide instead of 126

  N-{(E) -4- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -But-3-enyl} -methanesulfonamide was prepared in the same manner except that 1-butynol was replaced with but-3-en-1-ol in step 1 and hydrogenation (step 3) was omitted.

３−（６−ブロモ−３−tert−ブチル−４−メトキシ−ナフタレン−１−イル）−６−エチル−１Ｈ−ピリジン−２−オン（１３１）を、工程３で、８０の代わりに７５を使用した以外は、実施例８の工程１〜４に従って調製した。 Example 30
N- {3- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yloxy] -propyl}- Methanesulfonamide (I-45)

3- (6-Bromo-3-tert-butyl-4-methoxy-naphthalen-1-yl) -6-ethyl-1H-pyridin-2-one (131) was replaced with 75 instead of 80 in step 3. Prepared according to steps 1 to 4 in example 8 except that it was used.

Step 1-A solution of 70 dissolved in DMF was stirred with trimethyloxonium tetrafluoroboric acid at room temperature for 3 days. The resulting solution was washed sequentially with H ₂ O and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-5% EtOAc) to afford 132a.

Step 2—In a round bottom flask, 132a (0.1 g, 241 μmol), KOH (135 mg, 2.41 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′, 4 ′, 6′-Tri-isopropyl-1,1′-biphenyl (23.2 mg, 48.2 μmol), dioxane and water were added to obtain a colorless suspension. The mixture was sparged with nitrogen for 30 minutes, Pd ₂ (dba) ₃ was added, and sparging with N ₂ was continued for another 10 minutes. The reaction vessel was capped and heated at 100 ° C. for 20 hours. The reaction mixture was poured into EtOAc (50 mL) and washed sequentially with H ₂ O (20 mL) and brine (20 mL). The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by SiO ₂ chromatography eluting with EtOAc / hexane (30-60% EtOAc) to afford 70 mg (82.5% 132b).

Step 3-A flask was charged with 132b (120 mg, 340 μmol), 2-bromoethanol (213 mg, 1.7 mmol), K ₂ CO ₃ (94.1 mg, 681 μmol) and MeCN (5 mL) to give a colorless solution. . The reaction mixture was heated to 70 ° C. and stirred for 20 hours. The reaction mixture was poured into EtOAc (50 mL) and washed with H ₂ O (20 mL). The EtOAc layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient to give 100 mg (74.1%) of 134a.

Step 4-A flask is charged with 134a (100 mg, 252 μmol), tert-butylmethylsulfonyl carbamate (73.9 mg, 378 μmol), PPh ₃ (99.2 mg, 378 μmol) and THF (5 mL), and the solution is cooled in an ice bath. did. DEAD was added to the solution and the reaction mixture was stirred at room temperature for 20 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (20-60% EtOAc). The top spot (120 mg) was a 1: 1 mixture of product 134b and starting BocNHMs (UV non-absorbing, difficult to separate from each other) and 40 mg of 134a was recovered.

Step 5-A round bottom flask was charged with 134b (60 mg, 105 μmol), HBr (74.5 mg, 921 μmol) and HOAc (0.5 mL) from the previous step. The mixture was heated at 60 ° C. for 3 hours. The solution was cooled and diluted with H ₂ O (5 mL) and 4N NaOH (1 mL). The resulting solution was extracted with EtOAc (50 mL). The organic layer was washed sequentially with H ₂ O and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (50% to 100% EtOAc) followed by SiO ₂ chromatography eluting with 10% MeOH / EtOAc to give 30 mg (62.4). %) Of I-45.

工程１ − ＮａＨ分散物（２２６mg、５．６４mmol、６０％鉱油分散物）を、ヘキサン（３×１０mL）でトリチュレートし、Ｎ_２気流下で乾燥させ、ＴＨＦ（２３．５mL）に懸濁して、０℃に冷却した。３−ブロモ−２−メトキシ−６−（ヒドロキシメチル）ピリジン（０．８８ｇ、３．７９mmol）のＴＨＦ（１０mL）溶液を滴下し、混合物を３０分間撹拌した。溶液にＭｅＩ（１．００ｇ、４４１μL、７．０５mmol）を添加し、混合物を室温に温めた。１時間後、粗反応混合物を真空で濃縮し、混合物をＨ_２Ｏ（１００mL）に注ぎ、ＥｔＯＡｃ（３×５０mL）で抽出した。合わせた抽出物を、Ｈ_２Ｏ、食塩水で順次洗浄し、乾燥させ、濾過して、濃縮し、３−ブロモ−２−メトキシ−６−メトキシメチル−ピリジン（１３６）を明黄色の油状物として得た。 Example 32
N-{(S) -1- [6-tert-butyl-5-methoxy-8- (6-methoxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl ] -Pyrrolidin-3-ylmethyl} -methanesulfonamide (I-59)

Step 1—NaH dispersion (226 mg, 5.64 mmol, 60% mineral oil dispersion) was triturated with hexane (3 × 10 mL), dried under a stream of N ₂ , suspended in THF (23.5 mL), Cooled to 0 ° C. A solution of 3-bromo-2-methoxy-6- (hydroxymethyl) pyridine (0.88 g, 3.79 mmol) in THF (10 mL) was added dropwise and the mixture was stirred for 30 minutes. To the solution was added MeI (1.00 g, 441 μL, 7.05 mmol) and the mixture was allowed to warm to room temperature. After 1 hour, the crude reaction mixture was concentrated in vacuo and the mixture was poured into H ₂ O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed sequentially with H ₂ O, brine, dried, filtered and concentrated to give 3-bromo-2-methoxy-6-methoxymethyl-pyridine (136) as a light yellow oil. Got as.

Step 2 - To a round bottom _{flask, 136 (0.88g, 3.79mmol),} PdCl 2 (dppf). CH ₂ Cl ₂ (155 mg, 190 μmol), bis- (pinacolato) diboron (1.16 g, 4.55 mmol), KOAc (1.12 g, 11.4 mmol) and DMF were added. The light yellow solution was heated to 100 ° C. and stirred for 1 hour. The reaction mixture was cooled, poured into 50 mL H ₂ O and extracted with EtOAc / toluene (1: 1, 3 × 50 mL). The collected organic extracts were combined and washed sequentially with H ₂ O (50 mL) and brine (50 mL). The extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 2-methoxy-6- (methoxymethyl) -3- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) pyridine (138) was obtained and used without further purification.

Step 3-To a tube with a 10 mL screw cup, 118 (0.103 g, 219 μmol), PdCl ₂ (dppf). Put CH ₂ Cl ₂ (8.94 mg, 10.9 μmol), Cs ₂ CO ₃ (214 mg, 657 μmol), 138 (183 mg, 263 μmol), dioxane (1.75 mL) and H ₂ O (438 μL) and seal. And heated at 100 ° C. for 30 minutes. The reaction mixture was cooled, poured into H ₂ O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed sequentially with H ₂ O (50 mL) and brine (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (10-100% EtOAc) to yield 0.073 g (61%) of (S) -N-((1- (6-tert- Butyl-5-methoxy-8- (2-methoxy-6- (methoxymethyl) pyridin-3-yl) quinolin-3-yl) pyrrolidin-3-yl) methyl) methanesulfonamide (138) as a yellow foam Obtained as a thing.

Step 4-138 was demethylated according to the procedure of Step 7 of Example 2 to obtain I-32.

Example 33
N- {4- [6-tert-butyl-8- (5-fluoro-6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -Phenyl} -methanesulfonamide (I-47)
Step 1-To a flask containing 2,3,6-trifluoropyridine (2 g, 15 mmol) was added MeOH (5 mL) followed by methanolic NaOMe (5 mL, 25% NaOMe in MeOH). An exothermic reaction occurred and some solid was formed. The reaction was stirred for 10 minutes and diluted with H ₂ O. The solid was filtered, washed with _{H 2} O. The solid is dissolved in EtOAc, washed sequentially with water and brine, dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and 1.5 g (69%) of 3,6-difluoro. 2-Methoxy-pyridine (140) was obtained. The recovered material was used without further purification.

Step 2-To a THF solution of benzyl alcohol (1.12 g, 10.3 mmol) was added NaH (0.413 g, 10.3 mmol, 60% mineral oil dispersion) and stirred for 30 min. To this solution, 140 (1.5 g, 10.3 mmol) was added and the resulting solution was irradiated with a microwave synthesizer at 100 ° C. for 1 hour. The reaction was cooled, diluted with H ₂ O and extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by SiO ₂ chromatography to give 1 g (41%) of 6-benzyloxy-3-fluoro-2-methoxy-pyridine (142).

Step 3- 142 (1 g, 4.29 mmol) in DMF (10 mL) was cooled in an ice bath and NBS (0.763 g, 4.29 mmol) was added. The colorless mixture was stirred for 2 h and quenched with H 2 _O. The mixture was extracted with EtOAc (2 × 50 mL). The combined extracts were washed sequentially with H ₂ O and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography, 0.5 g of 6-benzyloxy-5-bromo-3-fluoro-2-methoxy - pyridine (144).

Step 3-N- {4- [6-tert-butyl-5-methoxy-8- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -quinoline-3 -Yl] -phenyl} -methanesulfonamide (146) can be prepared by condensation of 74b with bis- (pinacolato) diboron according to the procedure described in step b of Example 16.

Step 4—Into a microwave vial, 146 (1 eq), 144 (1 eq), Pd (PPh ₃ ) ₄ (0.1 eq), Na ₂ CO ₃ (3 eq), MeOH (9 mL) and DCM (3 mL) ), Sealed, and irradiated by a microwave synthesizer at 115 ° C. for 15 minutes. The reaction mixture was diluted with EtOAc and washed sequentially with H ₂ O and brine. The extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-20% EtOAc) to give 0.100 g of N- (4- (8- (2- (benzyloxy) -5- Fluoro-6-methoxypyridin-3-yl) -6-tert-butyl-5-methoxyquinolin-3-yl) phenyl) methanesulfonamide (148) was obtained.

Step 5—A mixture of 148 (0.100 g, 0.162 mmol), Pd / C (30 mg) and EtOAc was stirred under 1 atmosphere of hydrogen for 20 hours. The catalyst was filtered and washed with EtOAc. The filtrate was concentrated and the crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (30-80% EtOAc) to give 25 mg (29.3%) of I-47.

工程１ − １５０ａ（５．９３ｇ、１７．４mmol）、Ｐｄ（ＰＰｈ_３）_２Ｃｌ_２（６１０mg、８７０μmol）、ＣｕＩ（０．３３１ｇ、１．７４mmol）及びＴＨＦ（１７８mL）の溶液に、ＴＥＡ（１４．１ｇ、１９．４mL、１３９mmol）を添加した。反応混合物を、Ａｒを用いて脱気し、次に、３，３−ジメチル−ブタ−１−インを混合物に添加した。混合物を室温で一晩撹拌した後、エーテルで希釈し、Ｈ_２Ｏで洗浄した。有機抽出物を、２ＮのＨＣｌ及び飽和ＮａＨＣＯ_３水溶液で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過して、濃縮した。粗物質を、ＳｉＯ_２クロマトグラフィーによりＥｔＯＡｃ／ヘキサン（０〜１０％ ＥｔＯＡｃ）で溶離させて精製し、１５０ｂを得た。ＮＭＲから、生成物には出発物質が１０％含まれていた。 Example 34
N- {4- [3-tert-butyl-1- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -isoquinolin-6-yl] -phenyl} -methanesulfonamide ( I-48)

Step 1—To a solution of 150a (5.93 g, 17.4 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (610 mg, 870 μmol), CuI (0.331 g, 1.74 mmol) and THF (178 mL), TEA (14 0.1 g, 19.4 mL, 139 mmol) was added. The reaction mixture was degassed with Ar and then 3,3-dimethyl-but-1-yne was added to the mixture. The mixture was stirred at room temperature overnight then diluted with ether and washed with H ₂ O. The organic extract was washed with 2N HCl and saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by SiO ₂ chromatography eluting with EtOAc / hexanes (0-10% EtOAc) to afford 150b. From NMR, the product contained 10% starting material.

Step 2-Hydrolysis of 150b with methanolic NaOH under standard conditions to give 150c.

Step _{3 - 150c (4.58g, 16.3mmol)} , PdCl 2 (MeCN) 2 (1.63mmol), TEA (5.88g, 8.1mL, 58.1mmol) to a solution of and THF (320 mL), at room temperature And stirred overnight. The reaction mixture was diluted with Et ₂ O and washed sequentially with 10% HCl, H ₂ O, and saturated NaHCO ₃ . The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with a DCM / hexane gradient to give 2.47 g (53.9%) of 152a and a second fraction of a mixture of 152a and 152b.

Step 4-EtOH was placed in the flask and saturated with ammonia. To the solution was added 152a (2.47 g, 8.79 mmol) and the solution was irradiated with a microwave synthesizer at 130 ° C. for 5 hours. The reaction was cooled to room temperature and a white solid precipitated which was filtered and dried to give 1.849 g of 154a. The filtrate was concentrated to give 0.562 g of a 1: 1 mixture of 154a and 154b.

Step 5—A mixture of 154a (0.5 g, 1.78 mmol) and POCl ₃ (5 mL) was heated at 120 ° C. for 10 minutes. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaHCO ₃ solution. The reaction mixture was extracted with EtOAc and the combined extracts were washed with saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was dry loaded onto a SiO ₂ column and eluted with an EtOAc / hexane gradient (0-5% EtOAc) to give 0.5 g (93.8%) of 156.

Step 6—Into a vial, 156 (0.5 g, 1.67 mmol) and 25 (0.395 g, 1.84 mmol), Na ₂ CO ₃ (532 mg, 5.02 mmol), Pd (PPh ₃ ) ₄ (0.193 g 0.167 μmol), dioxane (3 mL) and H ₂ O (1 mL). The reaction mixture was heated to 80 ° C. and stirred overnight. The reaction mixture was filtered through glass fiber filter paper and the filtrate was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-50% EtOAc) to yield 0.38 g (58.4%) of 158 (Ar = 4-methanesulfonylamino-phenyl). Got.

Step 7—Into a vial, 158 (0.38 g, 977 μmol), 75 (326 mg, 1.95 mmol), Na ₂ CO ₃ (311 mg, 2.93 mmol), Pd (PPh ₃ ) ₄ (0.113 g, 97.7 μmol) ) And DME. The reaction mixture was heated to 80 ° C. and heated overnight. After 18 hours, 158 was still a little present. The reaction mixture was filtered through glass fiber filter paper and the filtrate was concentrated in vacuo. The crude material was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0-50% EtOAc) to give 0.120 g (25.8%) of 160.

Step 8-160 (0.12 g) was demethylated according to the procedure described in Step 7 of Example 2 to give 0.10 g (85.9%) of I-48. The product was precipitated and purified by washing with H ₂ O and Et ₂ O.

工程１ − 文献（J. Organomet. Chem. 2009 694:2493）の手順を用いて、１６２ａ（１当量）を、０℃で、ＮａＮＯ_２（３当量）及びＨＣｌのＨ_２Ｏ溶液と混合する。反応物を室温に温めて、１時間撹拌する。反応物を再び０℃に冷却し、ＳｎＣｌ_２（５当量）を添加する。反応物を室温で一晩温める。反応物をＤＣＭで希釈して、２ＮのＫＯＨで洗浄し、スズ塩を除去する。有機層を乾燥させ、真空で濃縮する。残渣を、ＳｉＯ_２のショートプラグを通してさらに精製し、１６２ｂを得た。 Example 35
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -cinnolin-3-yl] -phenyl} -methanesulfonamide ( 161)

Step 1—Using the procedure of the literature (J. Organomet. Chem. 2009 694: 2493), 162a (1 eq) is mixed at 0 ° C. with NaNO ₂ (3 eq) and HCl in H ₂ O. The reaction is warmed to room temperature and stirred for 1 hour. The reaction is again cooled to 0 ° C. and SnCl ₂ (5 eq) is added. The reaction is warmed at room temperature overnight. The reaction is diluted with DCM and washed with 2N KOH to remove the tin salt. The organic layer is dried and concentrated in vacuo. The residue was further purified through a short plug of SiO ₂ to give 162b.

Step 2-162b (1 eq), diethoxyacetyl chloride (1 eq, prepared from diethoxyacetic acid and SOCl ₂ ) and TEA (2 eq) in DCM are maintained at room temperature overnight. The reaction is washed with saturated aqueous NH ₄ Cl, dried and concentrated in vacuo. The resulting residue is dissolved in concentrated H ₂ SO ₄ at 0 ° C. and the reaction is warmed to room temperature and stirred for 20 hours. The reaction is neutralized with saturated aqueous NaHCO ₃ and extracted with DCM. The organic layer is dried and concentrated in vacuo and the residue is purified by SiO ₂ chromatography to afford 164.

Step 3—Dibromocinnoline 166 is obtained from a DMF solution of 164 (1 eq) and POBr ₃ (3 eq) using the procedure described in Step 3 of Example 36.

  Conversion of 166 to 161 is achieved by continuous palladium catalyzed coupling using 25 and 30.

工程１ − １６８ａ（１当量、Bull. Soc. Chim. Fr. 1969 6:2129）、ＮＢＳ（１当量）及びＡＩＢＮ（０．００５当量）及びベンゼンの溶液を、１４時間加熱還流する。反応物を室温に冷まし、固体沈殿物を濾過により除去する。ベンゼンを真空で除去し、得られた残渣をＮＨ_３／ＭｅＯＨ（４Ｍ）に溶解させ、室温で一晩撹拌する。溶媒を真空で除去し、残渣を、ＳｉＯ_２クロマトグラフィーにより精製し、１６８ｂを得る。 Example 36
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -isoquinolin-3-yl] -phenyl} -methanesulfonamide ( 174)

Step 1—A solution of 168a (1 equivalent, Bull. Soc. Chim. Fr. 1969 6: 2129), NBS (1 equivalent) and AIBN (0.005 equivalent) and benzene is heated to reflux for 14 hours. The reaction is cooled to room temperature and the solid precipitate is removed by filtration. Benzene is removed in vacuo and the resulting residue is dissolved in NH ₃ / MeOH (4M) and stirred at room temperature overnight. The solvent is removed in vacuo and the residue is purified by SiO ₂ chromatography to give 168b.

Step 2—A solution of 168b (1 eq), diethoxyacetyl chloride (1 eq, prepared from diethoxyacetic acid and SOCl ₂ ) and Et ₃ N (2 eq) in DCM is stirred at room temperature for 3 h. The reaction is washed with saturated aqueous NH ₄ Cl, dried and concentrated in vacuo. The resulting residue is dissolved in concentrated H ₂ SO ₄ at 0 ° C., then the reaction is warmed to room temperature and maintained for 28 hours. The reaction is neutralized with saturated aqueous NaHCO ₃ and extracted with DCM. The organic layer is dried and concentrated in vacuo and the residue is purified by SiO ₂ chromatography to give 170.

Step 3—170 (1 eq) and POBr ₃ (3 eq) in DMF are maintained at 90 ° C. for 2 h using the procedure of the literature (Chem, Lett. 2007 36 (8): 1036). The solution is cooled to room temperature, basified with 1N KOH solution and extracted with DCM. The combined extracts are washed with H ₂ O, dried, filtered and concentrated in vacuo. The residue is purified by SiO ₂ chromatography to give 172.

  Conversion of 172 to 174 is achieved by continuous palladium catalyzed coupling using 25 and 30.

工程１ − ６−ヒドロキシメチル−２−メトキシ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（dixaborolan）−２−イル）ピリジン（１７６、CASRN 1206776-83-1）を、１７４から、２，４−ジメトキシ−５−ブロモ−ピリミジンの代わりに１７４を使用した以外は実施例２６の手順に従って調製した。 Example 38
N- {4- [6-tert-butyl-8- (6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -phenyl} -Methanesulfonamide (I-41)

Step 1-6-hydroxymethyl-2-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (176, CASRN 1206776-83- 1) was prepared from 174 according to the procedure of Example 26 except that 174 was used instead of 2,4-dimethoxy-5-bromo-pyrimidine.

Step 2—Into the vial, 74b (0.125 g, 0.27 mmol), 176 (71 mg, 0.27 mmol), PdCl ₂ (dppf). Charge CH ₂ Cl ₂ (0.011 g, 0.05 mmol), Cs ₂ CO ₃ (0.269 g, 0.809 mmol), dioxane (2 mL) and H ₂ O (0.5 mL), degas and seal. And heated at 100 ° C. for 1 hour. The product was cooled and partitioned with EtOAc and _{H 2} O. The organic extract was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give 178, which was used without further purification.

Step 3-178 was demethylated according to the procedure of Step 7 of Example 2. The crude product was purified by preparative TLC plate development with 10% MeOH / DCM to give 3 mg of I-41.

６−tert−ブチル−３，８−ジブロモキノリン（１８０）を、２−ブロモ−４−tert−ブチルナフタレンから、実施例７の工程２の手順に従って、アクロレイン及び臭素を使用して調製する。１−ピロリジン−３−イルメチルメタンスルホンアミド部分の導入は、（Ｓ）−１−ピロリジン−３−イルメチル−カルバミン酸tert−ブチルエステルを用いて、実施例１９の工程１〜３の手順に従って行うことができる。ピリジン環の導入は、実施例２４の工程２の手順に従って、ブロモキノリン中間体と１１５とのSuzuki縮合、その後、実施例２２の工程６の手順に従って、メチルピリジニルエーテルの脱メチル化を行って、Ｉ−６０を得る。 Example 39
N-{(S) -1- [6-tert-butyl-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -pyrrolidine-3 -Ilmethyl} -methanesulfonamide (I-60)

6-tert-butyl-3,8-dibromoquinoline (180) is prepared from 2-bromo-4-tert-butylnaphthalene using acrolein and bromine according to the procedure of Example 2, Step 2. Introduction of the 1-pyrrolidin-3-ylmethylmethanesulfonamide moiety is performed according to the procedure of steps 1 to 3 of Example 19 using (S) -1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester. be able to. The pyridine ring was introduced by the Suzuki condensation of the bromoquinoline intermediate with 115 according to the procedure of Step 2 of Example 24, followed by the demethylation of methylpyridinyl ether according to the procedure of Step 6 of Example 22. I-60 is obtained.

標記化合物を、１８０から、実施例１３の工程２の手順に従って、SuzukiカップリングＩを用いて、メタンスルホニルアミノフェニル部分を導入することにより調製する。ジオキソ−テトラヒドロ−ピリミジン−１−イル置換体の合成は、実施例１７の工程１〜３の手順に従って行い、Ｉ−６１を得る。 Example 40
N- {4- [6-tert-butyl-8- (dioxo-tetrahydro-pyrimidin-1-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide (I-61)

The title compound is prepared from 180 by introducing the methanesulfonylaminophenyl moiety using Suzuki coupling I according to the procedure of Step 2 of Example 13. Synthesis of the dioxo-tetrahydro-pyrimidin-1-yl substituent is carried out according to the procedure of steps 17 to 3 of Example 17 to give I-61.

Example 41
HCV NS5B RNA polymerase activity The enzymatic activity of HCV polymerase (NS5B570n-Con1) was measured as the incorporation of radiolabeled nucleotide monophosphate into the acid-insoluble RNA product. Unincorporated radiolabeled substrate was removed by filtration and scintillant was added to the washed and dried filter plates containing the radiolabeled RNA product. At the end of the reaction, the amount of RNA product produced by NS5B570-Con1 was directly proportional to the amount of luminescence by scintillant.

  N-terminal 6-histidine-tagged HCV polymerase from HCV Con1 strain, genotype 1b (NS5B570n-Con1) contains a 21 amino acid deletion at the C-terminus with respect to full-length HCV polymerase. from the BL21 (DE) pLysS strain of E. coli. A construct containing the coding sequence of HCV NS5B Con1 (GenBank accession number AJ242654) was inserted downstream of the expression cassette of the T7 promoter of plasmid construct pET17b and transformed with E. coli. After a single colony was grown overnight as a starter culture, it was inoculated at 37 ° C. in 10 L LB medium supplemented with 100 μg / mL ampicillin. In 600 nM culture, when the optical density reached 0.6-0.8, 0.25 mM isopropyl-β-D-thiogalactopyranoside (IPTG) was added to induce protein expression, 30 ° C. Cells were harvested after 16-18 hours. NS5B570n-Con1 was purified and homogenized using a three step protocol involving continuous column chromatography of Ni-NTA, SP-Sepharose HP and Superdex 75 resin.

Each 50 μl enzyme reaction includes 20 nM RNA template derived from the complementary sequence of the internal ribosome entry site (cIRES), 20 nM NS5B570n-Con1 enzyme, 0.5 μCi tritiated UTP (Perkin Elmer, catalog number TRK-412; Specific activity: 30-60 Ci / mmol; stock solution concentration, 7.5 × 10 ⁻⁵ M to 20.6 × 10 ⁻⁶ M), 1 μM each of ATP, CTP and GTP, 40 mM Tris-HCl (pH 8.0) ), 40 mM NaCl, 4 mM DTT (dithiothreitol), 4 mM MgCl ₂ and 5 μl of the compound serially diluted with DMSO. The reaction mixture was collected in a 96 well filter plate (Catalog Number MADVN0B, Millipore Co.) and incubated at 30 ° C. for 2 hours. The reaction was stopped by adding 10% (v / v) final concentration of trichloroacetic acid and incubated at 4 ° C. for 40 minutes. The reaction was filtered, washed with 8 reaction volumes of 10% (v / v) trichloroacetic acid, 4 reaction volumes of 70% (v / v) ethanol, air dried and 25 μl scintillant (Microscint 20) in each reaction well. , Perkin-Elmer).

  Count the amount of light emitted from the scintillant with a Topcount (registered trademark) plate reader (Perkin-Elmer, energy range: low, efficiency mode: standard, count time: 1 minute, background subtraction: none, crosstalk reduction: off) / Converted to minutes (CPM).

をデータに当てはめて算出した。数式中、「Ｙ」は、相対酵素活性（％）に対応し、「％Ｍｉｎ」は、飽和化合物濃度における残存相対活性であり、「％Ｍａｘ」は、最大相対酵素活性であり、「Ｘ」は、化合物濃度に対応し、「Ｓ」は、Ｈｉｌｌ係数（又は傾き）に対応である。 Data were analyzed with Excel (registered trademark) (Microsoft (registered trademark)) and ActivityBase (registered trademark) (idbs (registered trademark)). The reaction in the absence of enzyme was used to determine the background signal, which was subtracted from the enzyme reaction. A positive control reaction was performed in the absence of compound, and background correction activity was now set as 100% polymerase activity. All data was expressed as a percentage of the positive control. The concentration of the compound at which the enzyme-catalyzed rate of RNA synthesis is reduced by 50% (IC ₅₀ ) is expressed as equation (i):

Was applied to the data. In the formula, “Y” corresponds to the relative enzyme activity (%), “% Min” is the residual relative activity at the saturated compound concentration, “% Max” is the maximum relative enzyme activity, and “X” Corresponds to the compound concentration, and “S” corresponds to the Hill coefficient (or slope).

Example 42
HCV Replicon Assay This assay measures the ability of a compound of Formula I to inhibit HCV RNA replication, ie its potential utility for the treatment of HCV infection. The assay utilizes the reporter as a simple readout for intracellular HCV replicon RNA levels. The Renilla luciferase gene is introduced into the first open reading frame of the genotype 1b replicon construct NK5.1, immediately after the internal ribosome entry (introduction) site (IRES) sequence (N. Krieger et al., J. Virol. 2001 75 (10): 4614), fused with neomycin phosphotransferase (NPTII) gene via self-cleaving peptide 2A derived from foot-and-mouth disease virus (MD Ryan & J. Drew, EMBO 1994 13 (4) : 928-933). After in vitro transcription, RNA was electroporated into human hepatocellular carcinoma Huh7 cells to isolate and grow G418 resistant colonies. The stably selected cell line 2209-23 contains replicating HCV subgenomic RNA, and the Renilla luciferase activity expressed by the replicon reflects its RNA level in the cell. To measure the antiviral activity and cytotoxicity of a compound in parallel, the assay was performed in duplicate plates, one of which was opaque white and the other was transparent, and was not due to reduced cell growth or cell death. The activity was confirmed.

HCV replicon cells (2209-23) expressing the Renilla luciferase reporter are cultured in Dulbecco's MEM (Invitrogen, catalog number 10569-010) supplemented with 5% fetal calf serum (FBS, Invitrogen, catalog number T10082-147) And seeded in 96-well plates at 5000 cells / well and incubated overnight. After 24 hours, various diluted compounds in growth medium were added to the cells, which were further incubated at 37 ° C. for 3 days. At the end of incubation, cells on white plates were harvested and luciferase activity was measured using the Renilla luciferase assay system (Promega, catalog number E2820). All reagents described in the following paragraphs were included in the manufacturer's kit and the reagents were prepared according to the manufacturer's instructions. Cells were washed once per well with 100 μl phosphate buffered saline (pH 7.0) (PBS), rinsed with 20 μl 1 × Renilla luciferase assay lysis buffer, and then incubated at room temperature for 20 minutes. The plate was then placed in a Centro LB 960 microplate luminometer (Berthold Technologies), 100 μl of Renilla luciferase assay buffer was injected into each well, and the signal was measured using a 2 second measurement program with a 2 second delay. . The IC ₅₀ , the drug concentration required to reduce the replicon level by 50% relative to the untreated cell control value, can be calculated from the percentage decrease in luciferase activity versus drug concentration plot described above.

For cytotoxicity assay, Roche Diagnostic's WST-1 reagent (catalog number 1644807) was used. 10 μl of WST-1 reagent was added to each well of a clear plate containing wells containing only medium as a blank. The cells were then incubated for 2 hours at 37 ° C. and the OD value at 450 nm (reference filter, 650 nm) was measured using an MRX Revelation microtiter plate reader (Lab System). Again, the CC ₅₀ , which is the drug concentration required to reduce cell proliferation by 50% with respect to the untreated cell control value, can be calculated from the percentage decrease in WST-1 value versus drug concentration plot above.

Example 43
Pharmaceutical compositions of the subject compounds for administration by several routes were prepared as described in this example.

  The ingredients were mixed and dispensed into capsules containing about 100 mg each; one capsule roughly corresponds to a total daily dose.

  The ingredients are mixed and powdered using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) using a suitable tablet machine.

  The ingredients are mixed to form a suspension for oral administration.

  The active ingredient is dissolved in a portion of water for injection. Next, a sufficient amount of sodium chloride is added with stirring to make the solution isotonic. The solution is brought to total weight with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under aseptic conditions.

  A feature or a method or process for achieving the disclosed results disclosed in a particular form or means for performing the disclosed function as disclosed in the foregoing description or in the claims below. If desired, such features can be used individually or in any combination to implement the invention in its various forms.

  For clarity and understanding, the above invention will now be described in detail by way of illustration and example. It will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. Accordingly, the scope of the invention should not be determined with reference to the foregoing description, but should be determined in conjunction with the appended claims and the full scope of equivalents to which such claims are entitled. Is.

  The patents, published patent applications and scientific literature cited in this application establish the knowledge of those skilled in the art, thereby making it as if each was specifically and individually incorporated by reference. Are incorporated by reference in their entirety to the same extent as shown in In the event of any discrepancy between any reference cited herein and the specific teachings herein, the latter shall be resolved in favor of the latter. Similarly, if there is any discrepancy between a language or phrase definition as understood in the art and a language or phrase definition as specifically taught herein, the latter will be resolved in preference. Shall.

Claims (28)

Formula I:

[Where:
X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ ;
X ¹ and X ² are N and X ³ and X ⁴ are CR ⁵ ;
X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N;
X ¹ and X ⁴ are N and X ² and X ³ are CR ⁵ ;
X ¹ , X ² , X ³ and X ⁴ are CR ⁵ ;
R ¹ represents (a) pyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro -Pyridazin-4-yl, 2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl, 6-oxo-1,6-dihydro- [1,2,4] triazin-5-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, 2-oxo-2 (H) -pyridin-1-yl, 6-oxo-6H-pyridazin-1-yl, 6-oxo A heteroaryl group selected from the group consisting of -6H-pyrimidin-1-yl and 2-oxo-2H-pyrazin-1-yl, wherein the heteroaryl is halogen, C _1-6 alkyl, C _1-3 Haloalkyl, C _1-6 hydro Optionally by xyalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 alkoxy, X ¹ (CH ₂ ) _1-6 CO ₂ H or X ^1- (CH ₂ ) _2-6 NR ^g R ^h Has been replaced, or
(B) 2-oxo-tetrahydro-pyrimidin-1-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2,6- Dioxo-tetrahydro-pyrimidin-1-yl, 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and 2,5-dioxo-imidazolidin-1-yl and 2,4-dioxo -A heterocyclic group selected from the group consisting of tetrahydro-pyrimidin-1-yl;
R ² is hydrogen, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy or halogen;
R ³ is (a) aryl, (b) heteroaryl, wherein the aryl or heteroaryl is hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 hydroxyalkyl, halogen, ( _{^{CH 2) n NR c R d}} , _{cyano, C 1-6} alkoxycarbonyl, carbamoyl, N- alkylcarbamoyl, n, N- _{dialkylcarbamoyl, (CH 2) 0-3 CO 2} H, SO 2 NH 2, C 1 Optionally substituted independently by 1 to 3 substituents selected from the group consisting of _-6 alkylsulfinyl and C _1-6 alkylsulfonyl, or (c) NR ^a R ^b , (d) hydrogen , (E) halogen, (f) -X (R ⁷ ) [C (R ⁶ )] _2-6 NR ^e R ^f (wherein X is O) or NR ⁷ , R ⁷ is hydrogen or C _2-4 alkyl, and R ⁶ is independently hydrogen, C _1-3 alkyl for each occurrence, or two R ⁶ residues on the same carbon are C _2-5 alkylene, or two R ⁶ residues on different carbons are C _1-4 alkylene);
R ^a and R ^b , together with the nitrogen to which they are attached, are independent of 1 to 3 groups independently selected from C _1-6 alkyl, halogen, or (CH ₂ ) _n NR ^e R ^f A substituted cyclic amine;
R ^c and R ^d are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 acyl, SO ₂ R ⁸ , R ⁸ is (a) C _1-6 alkyl (B) C _1-6 haloalkyl, (c) C _3-7 cycloalkyl, (d) C _3-7 cycloalkyl-C _1-3 alkyl, (e) C _1-6 alkoxy-C _1-6 alkyl Or (f) SO ₂ [C (R ⁹ ) ₂ ] _0-6 NR ^k R ^l , C _1-3 alkylcarbamoyl or C _1-3 dialkylcarbamoyl;
R ^e and R ^f are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 acyl, SO ₂ R ⁸ , R ⁸ is (a) C _1-6 alkyl (B) C _1-6 haloalkyl, (c) C _3-7 cycloalkyl, (d) C _3-7 cycloalkyl-C _1-3 alkyl, (e) C _1-6 alkoxy-C _1-6 alkyl Or (f) SO ₂ [C (R ⁹ ) ₂ ] _0-6 NR ^k R ^l ;
R ⁱ and R ^j are (i) independently hydrogen, C _1-3 alkyl or (CH ₂ ) _2-6 NR ^g R ^h , or (ii) together with the nitrogen to which they are attached. (CH ₂ ) ₂ X ⁵ (CH ₂ ) ₂ , X ⁵ is O or NR ^k , and R ^k is hydrogen, C _1-3 alkyl, C _1-3 acyl or C _1-3 alkylsulfonyl;
R ⁴ is hydrogen, CF ₃ , CH ₂ CF ₃ , C _3-5 cycloalkyl, halogen, C _1-6 alkoxy, C _1-3 haloalkoxy, CHR ^4a R ^4b or CR ^4a R ^4b R ^4c , Where
(I) R ^4a , R ^4b and R ^4c are independently selected from C _1-3 alkyl, CD ₃ , C _1-2 alkoxy, C _1-2 fluoroalkyl, C _1-3 hydroxyalkyl, cyano or hydroxy Or
(Ii) when taken together, R ^4a and R ^{4b taken} together are C _2-4 alkylene and R ^4c is hydrogen, C _1-3 alkyl, C _1-2 alkoxy, halogen, C _1-3 hydroxyalkyl, cyano or C _1-2 fluoroalkyl or R ^4a and R ^4b together with the carbon to which they are attached are 3-oxetanyl or tetrahydrofuran-2-yl ;
R ⁵ is independently for each occurrence hydrogen, halogen, C _1-6 alkoxy or C _1-6 alkyl;
R ⁸ , R ^g and R ^h are independently hydrogen or C _1-3 alkyl for each occurrence;
R ^k and R ^l are (i) independently for each occurrence hydrogen or C _1-6 alkyl, or (ii) together with the nitrogen to which they are attached, R ^k and R ^l are Forming a cyclic amine;
n is 0 to 3 independently for each occurrence]
Or a pharmaceutically acceptable salt thereof. X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ and R ³ is (a) substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d The compound of claim 1, wherein n is 0 or (b) NR ^a R ^b . 2-oxo-1,2-dihydro-pyridin-3-yl or 2,4, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy -Dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and R ³ is at least (CH ₂ ) The compound according to claim 2, which is phenyl substituted at the 4-position by _n NR ^c R ^d , and n is 0 or 1. R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine, or R ^4a and R ^4b together It turned to a _{C 2} alkylene, and is a ^{(b) R 4c} _{is, C 1-3 alkyl, C 1-2} alkoxy, _{halogen, C 1-3} hydroxyalkyl, cyano or _{C 1-2} perfluoroalkyl, The compound according to claim 3. R ³ is NR ^a R ^b and R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine Or R ^4a and R ^{4b taken} together are C ₂ alkylene, and (b) R ^4c is C _1-3 alkyl, C _1-2 alkoxy, halogen, C _1-3 hydroxy 3. A compound according to claim 2, which is alkyl, cyano or _C1-2 fluoroalkyl. NR ^a R ^b together is a cyclic amine substituted by (CH ₂ ) _n NR ^e R ^f , where n is 0-2; and R ^e and R ^f _Are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, SO ₂ R ⁸ , and R ⁸ is (a) C _1-6 alkyl, (b) C _1-6 haloalkyl, ( _{c) C 3-7} cycloalkyl, _{(d) C 3-7} cycloalkyl _{-C 1-3} alkyl, _{(e) C 1-6} alkoxy _{-C 1-6} alkyl, a compound according to claim 5. R ³ is phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , n is 0, and R ¹ is 6-oxo-1,6-dihydro- [ 3. A compound according to claim 2, which is 1,2,4] triazin-5-yl. R ³ is phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , n is 0, and R ¹ is 2-oxo-tetrahydro-pyrimidin-1-yl The compound of claim 2, wherein X ¹ and X ² are N and X ³ and X ⁴ are CR ⁵ and R ³ is (a) substituted at position 4 by at least (CH ₂ ) _n NR ^c R ^d The compound of claim 1, wherein n is 0 or (b) NR ^a R ^b . 2-oxo-1,2-dihydro-pyridin-3-yl or 2,4, wherein R ¹ is optionally substituted by halogen, C _1-6 alkyl, C _1-3 haloalkyl or C _1-6 alkoxy -Dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and R ³ is at least (CH ₂ ) The compound according to claim 9, which is phenyl substituted at the 4-position by _n NR ^c R ^d , and n is 0 or 1. R ⁴ is CR ^4a R ^4b R ^4c and (a) R ^4a , R ^4b and R ^4c are CH ₃ , CD ₃ or fluorine, or R ^4a and R ^4b together It turned to a _{C 2} alkylene, and is a ^{(b) R 4c} _{is, C 1-3 alkyl, C 1-2} alkoxy, _{halogen, C 1-3} hydroxyalkyl, cyano or _{C 1-2} fluoroalkyl, 11. A compound according to claim 10. NR ^a R ^b together is a cyclic amine substituted by (CH ₂ ) _n NR ^e R ^f , where n is 0-2; and R ^e and R ^f _Are independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, SO ₂ R ⁸ , and R ⁸ is (a) C _1-6 alkyl, (b) C _1-6 haloalkyl, ( _{c) C 3-7} cycloalkyl, _{(d) C 3-7} cycloalkyl _{-C 1-3} alkyl, _{(e) C 1-6} alkoxy _{-C 1-6} alkyl, a compound according to claim 9. The compound of claim ¹ , wherein X ¹ , X ² and X ⁴ are CR ⁵ and X ³ is N. R ³ is (a) phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d , and n is 0 or (b) NR ^a R ^b Item 14. The compound according to Item 13. The compound of claim ^1, wherein X ¹ and X ⁴ are N and X ² and X ³ are CR ⁵ . R ³ is (a) phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , and n is 0 or (b) NR ^a R ^b Item 15. The compound according to Item 15. The compound of claim ¹ , wherein X ¹ , X ² , X ³ and X ⁴ are CR ⁵ . R ³ is (a) phenyl substituted at least in position 4 by (CH ₂ ) _n NR ^c R ^d , and n is 0 or (b) NR ^a R ^b Item 18. The compound according to Item 17. X ¹ is N and X ² , X ³ and X ⁴ are CR ⁵ and R ¹ is 2,6-dioxo-tetrahydro-pyrimidin-1-yl, 2,5-dioxo-imidazo Ridin-1-yl or 2,4-dioxo-tetrahydro-pyrimidin-1-yl; and R ³ is (a) phenyl substituted at the 4-position by at least (CH ₂ ) _n NR ^c R ^d And n is 0 or (b) NR ^a R ^b . 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the list consisting of:
N- {4- [6-tert-butyl-2-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide;
N- {1- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -piperidin-4-yl} -methanesulfonamide;
N-{(S) -1- [7-tert-butyl-5- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -pyrrolidine-3 -Ylmethyl} -methanesulfonamide;
N- {1- [7-tert-butyl-5- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -piperidin-4-yl}- Methanesulfonamide;
N- {4- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-chloro-phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-fluoro-phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-chloro-phenyl}- Methanesulfonamide;
N- {4- [7-tert-butyl-3-methyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-fluoro-phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-8- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {1- [6-tert-butyl-8- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -piperidin-4-yl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide;
3- (3-bromo-6-tert-butyl-5-methoxy-quinolin-8-yl) -1H-pyridin-2-one;
3- (6-tert-butyl-5-methoxy-quinolin-8-yl) -1H-pyridin-2-one;
N-{(S) -1- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -pyrrolidine-3 -Ylmethyl} -methanesulfonamide;
N- {1- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -azetidin-3-ylmethyl}- Methanesulfonamide;
N- [4- (8-Bromo-6-tert-butyl-5-methoxy-quinolin-3-yl) -phenyl] -methanesulfonamide;
N- {4- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide;
N- {1- [6-tert-butyl-4-chloro-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -azetidine-3 -Ylmethyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-8- (2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -5-methoxy-quinolin-3-yl] -phenyl } -Methanesulfonamide;
N- {4- [6-tert-butyl-8- (3-fluoro-pyridin-4-yl) -5-methoxy-quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-tetrahydro-pyrimidin-1-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [8- (2,4-Dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-6-trifluoromethyl-quinolin-3-yl] -phenyl} -methanesulfonamide;
N-{(S) -1- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -Pyrrolidin-3-ylmethyl} -methanesulfonamide;
N- {4- [6- [1,1-di (methyl-d ₃ ) ethyl-2,2,2-d ₃ ] -5-methoxy-8- (2-oxo-1,2-dihydro-pyridine) -3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide; and
N- {4- [8- (Dioxo-tetrahydro-pyrimidin-1-yl) -5-methoxy-6- (2,2,2-trifluoro-ethyl) -quinolin-3-yl] -phenyl} -methane Sulfonamide. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the list consisting of:
N- {4- [6-tert-butyl-2-methoxy-3- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-8-yl] -phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (4-methanesulfonylamino-phenyl) -quinoxalin-2-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -5-methoxy-quinolin-3-yl] -phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
2- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -benzoic acid;
N- {4- [7-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -3-methyl-quinoxalin-2-yl] -3-chloro -Phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-3-methyl-5- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-chloro -Phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinoxalin-2-yl] -3-cyano-phenyl} -methanesulfonamide;
N- {4- [7-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -quinoxalin-2-yl] -3-cyano-phenyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (3-methyl-5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -quinoline-3 -Yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -2-fluoro-phenyl}- Methanesulfonamide;
N-{(S) -1- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -pyrrolidine-3 -Ylmethyl} -methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -morpholin-2-ylmethyl}- Methanesulfonamide;
N- {1- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -piperidin-3-ylmethyl}- Methanesulfonamide;
2- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -5-methanesulfonylamino-benzoic acid methyl ester ;
N- {4- [8- (4-Methanesulfonylamino-phenyl) -5-methoxy-6-trifluoromethyl-quinolin-3-yl] -phenyl} -methanesulfonamide;
N- [6-tert-butyl-3- (4-methanesulfonylamino-phenyl) -5-methoxy-quinolin-8-yl] -acetamide;
2- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -5-methanesulfonylamino-benzoic acid;
N- {4- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -morpholin-2-ylmethyl}- Methanesulfonamide;
N- {1- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -3-methyl-pyrrolidine-3 -Ylmethyl} -methanesulfonamide;
N- {3- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -prop-2 -Inyl} -methanesulfonamide;
N- {3- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -propyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -buta-3 -Inyl} -methanesulfonamide;
N- (3-{[6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -methanesulfonyl -Amino} -propyl) -methanesulfonamide;
Prop-2-ene-1-sulfonic acid {4- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinoline- 3-yl] -phenyl} -amide;
2,3-dihydroxy-propane-1-sulfonic acid {4- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)- Quinolin-3-yl] -phenyl} -amide;
N- {5- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -furan-2-ylmethyl}- Methanesulfonamide;
N- {4- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -buta-3 -Inyl} -methanesulfonamide;
N- {1- [6-tert-butyl-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -4,4-dimethyl-pyrrolidine -3-ylmethyl} -methanesulfonamide;
N- {1- [6-tert-butyl-5-methoxy-8- (6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -3-methyl -Pyrrolidin-3-ylmethyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -phenyl} -Methanesulfonamide;
N-{(E) -4- [6-tert-butyl-5-methoxy-8- (6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl] -But-3-enyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (dioxo-tetrahydro-pyrimidin-1-yl) -quinolin-3-yl] -phenyl} -methanesulfonamide;
N- {4- [6-tert-butyl-8- (5-fluoro-2-methoxy-6-oxo-1,6-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl] -Phenyl} -methanesulfonamide;
N-{(S) -1- [6-tert-butyl-5-methoxy-8- (6-methoxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl) -quinolin-3-yl ] -Pyrrolidin-3-ylmethyl} -methanesulfonamide; and
N-{(S) -1- [6-tert-butyl-8- (6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl) -5-methoxy-quinolin-3-yl ] -Pyrrolidin-3-ylmethyl} -methanesulfonamide.   A method for treating a hepatitis C virus (HCV) infection comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.   23. The method of claim 22, further comprising co-administering at least one immune system modulating agent and / or at least one antiviral agent that inhibits HCV replication.   A method for inhibiting HCV replication in a cell by delivering a compound according to claim 1.   Use of a compound of formula I as claimed in claim 1 for the treatment of HCV infection.   26. Use according to claim 25 of a compound of formula I in combination with at least one immune system modulator and / or at least one antiviral agent that inhibits HCV replication for the treatment of HCV infection.   Use of a compound of formula I for the manufacture of a medicament for the treatment of HCV infection.   A composition comprising a compound according to claim 1 in admixture with at least one pharmaceutically acceptable carrier, diluent or excipient.